Fact-checked by Grok 2 weeks ago

Gap junction

Gap junctions are specialized plasma membrane channels that form direct connections between the cytoplasm of adjacent animal cells, enabling the intercellular exchange of ions, second messengers, and small hydrophilic metabolites with molecular weights up to approximately 1.2 kDa.^[1] These structures, also known as nexus junctions, were first identified in the 1950s through electron microscopy as regions where cell membranes are closely apposed with a narrow extracellular gap of 2–4 nm.^[2] In vertebrates, gap junctions are primarily composed of connexin proteins, a family of at least 21 isoforms in humans, while invertebrates utilize analogous innexin proteins.^[3] Each functional channel arises from the docking of two hemichannels, or connexons, where six connexin subunits oligomerize to form a transmembrane pore approximately 1.5 nm in diameter.^[2] The assembly of gap junctions begins in the endoplasmic reticulum, where connexins fold and traffic through the Golgi apparatus before being inserted into the plasma membrane via vesicular transport.^[1] Once at the membrane, connexons from opposing cells align and dock via interactions between their extracellular loops, forming dense plaques that can contain hundreds to thousands of channels.^[2] Connexins are characterized by four transmembrane α-helices, two extracellular loops, a cytoplasmic loop, and intracellular N- and C-terminal domains, with isoform-specific variations influencing channel selectivity, gating, and permeability.^[1] For instance, connexin 43 (Cx43), the most widely expressed isoform found in over 50% of human cell types, facilitates rapid turnover with a half-life of about 1–2 hours and is degraded via lysosomal pathways.^[4] Functionally, gap junctions mediate both electrical coupling—through the flow of ions like K⁺ and Ca²⁺—and metabolic coupling—via diffusion of molecules such as cAMP, IP₃, and glucose—allowing synchronized cellular activities essential for tissue development, homeostasis, and response to injury.^[1] In excitable tissues like the heart and brain, they propagate action potentials and synchronize oscillations, as seen with Cx36 in neuronal gap junctions supporting gamma rhythms critical for cognition.^[2] In non-excitable tissues such as the epidermis and lens, they ensure coordinated differentiation and nutrient distribution.^[1] Additionally, undocked hemichannels can release signaling molecules into the extracellular space, contributing to processes like wound healing and inflammation, though dysregulation may promote pathologies.^[4] Mutations in connexin genes underlie numerous human diseases, highlighting their physiological importance; for example, Cx26 defects cause nonsyndromic deafness, while Cx32 mutations are linked to Charcot-Marie-Tooth neuropathy.^[2] Recent structural advances, including cryo-electron microscopy resolutions down to 1.9 Å for channels like Cx46/50, have revealed conformational states (open/closed) and lipid interactions that modulate gating via phosphorylation at multiple residues on Cx43.^[4] These insights underscore gap junctions' role in intercellular communication across all major human organ systems, from cardiac rhythmicity to glial support in the central nervous system.^[4]

Molecular Structure and Composition

Connexins and Connexons

Connexins constitute a family of approximately 21 integral membrane proteins in humans, encoded by genes primarily in the GJA (alpha), GJB (beta), and GJC (gamma) subfamilies, which serve as the fundamental building blocks of gap junctions in vertebrates.^[5] These proteins are named based on their predicted molecular weights, ranging from 25 to 60 kDa, and exhibit a conserved topological structure consisting of four α-helical transmembrane domains, two extracellular loops, one intracellular loop, and intracellular N- and C-termini.^[6] The N-terminus is highly conserved across isoforms, while the C-terminus varies significantly in length and sequence, influencing protein interactions and regulation.^[6] A connexon, or hemichannel, forms when six connexin subunits oligomerize into a cylindrical assembly, creating a transmembrane channel with a central aqueous pore of approximately 1.2 nm in minimum diameter.^[7] This hexameric structure is typically homomeric (composed of identical connexins) but can also be heteromeric when incorporating different isoforms, allowing for diverse channel properties.^[6] The extracellular loops of connexins contain three conserved cysteine residues each, which form disulfide bonds critical for stabilizing the protein and facilitating interactions between hemichannels.^[6] Connexin isoforms display distinct tissue-specific expression patterns, contributing to specialized intercellular communication. For instance, connexin-43 (Cx43, encoded by GJA1, ~43 kDa) is ubiquitously expressed in tissues such as heart, brain, and skin, while connexin-32 (Cx32, encoded by GJB1, ~32 kDa) predominates in liver and Schwann cells.^[6] These variations extend to post-translational modifications, notably phosphorylation, which occurs primarily on serine and tyrosine residues in the C-terminal tail; Cx43 alone has at least 14 such sites targeted by kinases like MAPK and PKC, modulating protein stability and trafficking.^[8] In contrast, invertebrates employ innexins as structural analogues, though vertebrate connexins form the focus here.^[5]

Gap Junction Formation and Plaques

Gap junctions form when preassembled connexons, or hemichannels, from the plasma membranes of adjacent cells dock end-to-end in a head-to-head configuration, creating complete intercellular channels that span the two membranes across an extracellular gap of 2-4 nm.^[9] This docking is mediated by specific interactions between the extracellular loops of the connexin proteins, ensuring compatibility between the hemichannels and forming a stable conduit for intercellular exchange.^[10] The resulting structure maintains the narrow gap, which is visible in electron micrographs as a clear space between the apposed membranes.^[11] These individual channels aggregate laterally to form gap junction plaques, which are extensive, crystalline arrays typically containing hundreds to thousands of channels organized in a hexagonal lattice.^[11] Plaques vary in size, often reaching diameters of several micrometers, and serve as the primary organizational unit for gap junctions in tissues.^[9] Channel density within plaques can reach up to approximately 10,000 channels per μm² in densely packed regions, such as those observed in cardiac or hepatic tissues, contributing to the plaques' high efficiency in coupling.^[12] Turnover of these plaques is dynamic, with connexins exhibiting half-lives of 1-5 hours, involving continuous addition of new channels at the periphery and removal from the center through endocytic processes.^[11] The initial assembly of gap junctions occurs within specialized plasma membrane domains known as formation plaques, where connexons first insert and cluster before docking with opposing hemichannels.^[12] These formation plaques act as nucleation sites, facilitating the matching of apposed membranes and the progressive aggregation of particles into mature structures.^[11] Connexons are trafficked to these sites via microtubules, with post-Golgi vesicles carrying the hemichannels along cytoskeletal tracks to the plasma membrane, enabling targeted delivery and insertion.^[13] Ultrastructurally, gap junction plaques appear in electron microscopy as regions of closely apposed plasma membranes exhibiting a pentalaminar profile, with the 2-4 nm gap evident between the inner and outer leaflets.^[11] Freeze-fracture electron microscopy reveals the plaques as dense arrays of intramembranous particles, approximately 10 nm in diameter, arranged in ordered, often hexagonal patterns that correspond to the embedded connexons.^[14] These particle arrays highlight the crystalline organization, with densities increasing during plaque maturation as individual connexons aggregate.^[12] Different connexin isoforms can contribute to the composition of plaques, allowing for heterotypic or heteromeric channel arrangements in compatible tissues.^[9]

Biophysical Properties

Channel Permeability and Gating

Gap junction channels permit the passage of small ions, including potassium (K⁺) and calcium (Ca²⁺) ions, as well as second messengers such as inositol trisphosphate (IP₃) and cyclic adenosine monophosphate (cAMP), and metabolites like ATP and glucose, facilitating direct intercellular exchange of these molecules.^[15] These channels exclude larger biomolecules, such as proteins and nucleic acids, due to a size exclusion limit typically around 1 kDa for globular molecules, though this varies by connexin isoform; for instance, channels formed by connexin 43 (Cx43) and connexin 32 (Cx32) exhibit higher permeability to probes up to 760 Da compared to those formed by Cx26 or Cx37.^[16] Permeability is influenced by both size and charge selectivity, with Cx43 channels showing relatively weak charge discrimination while Cx40 and Cx26 favor cationic probes over anionic ones of similar size.^[15] The unitary conductance of individual gap junction channels, measured via patch-clamp techniques in paired cells, typically ranges from 50 to 100 pS depending on the connexin; for example, Cx43 channels in astrocytes display a consistent open-state conductance of approximately 50-60 pS.^[17] Seminal patch-clamp studies on invertebrate and vertebrate gap junctions have resolved these discrete single-channel currents, revealing step-like transitions between open and closed states under voltage control.^[18] Channel conductance G is calculated as G = \frac{I}{V_j}, where I is the junctional current and V_j is the transjunctional voltage, allowing quantification of ionic flow through the pore.^[19] Gating of gap junction channels involves multiple mechanisms that regulate channel opening and closure. Voltage-dependent gating responds to transjunctional voltage (V_j), the potential difference across the junction, with steady-state conductance (G_{ss}) exhibiting a characteristic bell-shaped dependence on V_j, peaking near 0 mV and declining symmetrically at higher magnitudes (e.g., half-inactivation around ±60 mV for cardiac Cx43 channels), often fitted by a two-state Boltzmann relation that reflects fast and slow gate transitions to residual or fully closed states.^[20] Chemical gating is triggered by intracellular changes, such as acidification (low pH) or elevated Ca²⁺ levels, which promote slow closure through protonation of key residues or calmodulin interactions, reducing conductance to near zero.^[19] Mechanical sensitivity arises from membrane tension or stretch, as demonstrated in cochlear supporting cells where increased turgor pressure (e.g., ~1.4 kPa) decreases transjunctional conductance by up to 40% via direct modulation of channel conformation, a process often reversible upon tension relief.

Regulation of Connexons and Hemichannels

Post-translational modifications play a critical role in regulating the assembly, activity, and turnover of connexons and hemichannels. Phosphorylation, particularly on the C-terminal tail of connexin 43 (Cx43), modulates these processes; for instance, protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) phosphorylate specific serine residues, influencing channel gating and intercellular communication. Dephosphorylation events counteract these effects, promoting channel opening, while ubiquitination targets Cx43 for degradation, thereby controlling the stability and turnover of gap junction plaques. These modifications collectively fine-tune connexon function in response to cellular signals. Trafficking of connexins is tightly regulated to ensure proper insertion and removal from the plasma membrane. Connexins are synthesized and co-translationally inserted into the endoplasmic reticulum (ER), then trafficked through the Golgi apparatus to the cell surface where they assemble into hemichannels. Internalization occurs via clathrin-mediated endocytosis, often triggered by ubiquitination, leading to lysosomal degradation or recycling. Cx43 exhibits a notably short half-life of 1-5 hours, which facilitates rapid turnover and adaptation to changing cellular needs. Interactions with scaffolding proteins and lipids further modulate connexon and hemichannel activity. The scaffolding protein zonula occludens-1 (ZO-1) binds to the C-terminus of Cx43 via its PDZ domain, stabilizing gap junctions at cell-cell contacts and regulating plaque size and organization. Lipid composition in the membrane environment also influences channel behavior; for example, incorporation into lipid rafts rich in sphingomyelin and cholesterol can alter connexon gating and assembly, while polyunsaturated fatty acids directly interact with connexins to promote or inhibit channel opening. Environmental factors such as temperature, osmolarity, and oxidative stress impact connexon regulation. Elevated temperatures impair gap junction communication by altering phosphorylation states and reducing conductance in cardiac and epithelial cells. Changes in osmolarity, particularly hypertonicity, enhance gap junction-mediated osmolyte exchange, aiding cellular volume regulation and adaptation in renal epithelia. Oxidative stress promotes hemichannel opening through cysteine oxidation and downstream signaling, facilitating ATP release but potentially leading to uncontrolled permeability if prolonged. Recent structural advances, including cryo-electron microscopy (cryo-EM) studies post-2020, have elucidated gating conformations of connexons. High-resolution cryo-EM structures of Cx36 and Cx46/50 reveal open and closed states, highlighting dynamic helix movements in response to stimuli. Computational analyses in 2025 have proposed a "molecular grammar" governing isoform compatibility, predicting docking interfaces that determine heterotypic channel formation based on sequence motifs. These insights underscore how regulatory mechanisms integrate with structural dynamics to control intercellular coupling.

Tissue Distribution and Expression

Expression in Vertebrate Tissues

Gap junctions, formed by connexin proteins, are ubiquitously expressed across vertebrate tissues, enabling intercellular communication in both excitable and non-excitable cell types, with notable exceptions in mature red blood cells, platelets, and certain mature neurons.^[21] This widespread distribution underscores their role in coordinating cellular activities in diverse organs, where specific connexin isoforms predominate based on tissue requirements.^[22] In the heart, gap junctions exhibit high density, primarily composed of connexin 43 (Cx43) and connexin 40 (Cx40), which are the dominant isoforms in cardiomyocytes of mammalian species. Cx43 is the most abundant, forming the majority of gap junction plaques in ventricular myocardium, while Cx40 is enriched in atrial and conduction system tissues, as demonstrated by immunohistochemistry showing regional variations in protein localization.^[23]^[24] Quantitative assessments via Western blot and immunofluorescence in rodent models indicate Cx43 protein levels constitute over 90% of total connexin content in ventricular tissue, highlighting its prevalence.^[25] The liver displays prominent expression of connexin 32 (Cx32), which is constitutively present in hepatocytes across vertebrate species, including rodents and humans, forming extensive gap junction networks that span liver lobules. Immunohistochemical studies reveal uniform Cx32 distribution in hepatocyte membranes.^[26] This isoform's steady expression supports coordinated metabolic functions in hepatic parenchyma.^[27] In the brain, connexin 36 (Cx36) is the primary isoform expressed in neuronal populations throughout the central nervous system of mammals, localizing to gap junctions between interneurons and principal neurons in regions such as the hippocampus, inferior olive, and retina. In situ hybridization and immunolabeling confirm Cx36's neuronal specificity, with protein detection restricted to puncta at synaptic sites.^[28]^[29] Developmental regulation of gap junction expression is dynamic, with transient upregulation during embryogenesis; for instance, Cx43 is prominently expressed in premigratory neural crest cells, facilitating their migration and differentiation in avian and mammalian models. Transgenic studies using Cx43 promoter-driven reporters demonstrate its localization to neural folds and crest streams during early organogenesis, with expression peaking around embryonic day 8.5 in mice before regional downregulation.^[30]^[31] Such patterns reflect connexin isoforms' tissue-specific orchestration during development.^[32] Species variations in expression are evident, particularly in non-mammalian vertebrates; in teleost fish like zebrafish and perch, connexin 35 (Cx35, orthologous to mammalian Cx36) shows heightened expression in retinal neurons, including photoreceptors and bipolar cells, where it forms extensive networks not as pronounced in mammalian retinas. Immunolabeling in fish retina reveals Cx35 puncta at higher density in the outer plexiform layer compared to mammalian counterparts, underscoring adaptive differences in visual processing.^[33]^[34] Recent single-cell RNA-sequencing studies in the 2020s have revealed enhanced cell-type specificity in connexin expression across vertebrates, such as in developing zebrafish where Cx43 and Cx40 orthologs are enriched in cardiac progenitors, while Cx36-like isoforms predominate in neuronal clusters, providing granular maps of isoform distribution unattainable by bulk methods.^[35] These profiles confirm conserved patterns across mammals and fish but highlight subtle divergences in neural and cardiac lineages.^[36]

Analogues in Invertebrates

In invertebrates, gap junctions are formed by proteins known as innexins, which serve as structural and functional analogues to vertebrate connexins.^[37] Innexins assemble into hexameric structures called innexons that dock between adjacent cells to create intercellular channels, enabling direct communication similar to connexons in vertebrates.^[38] Despite this functional parallelism, innexins and connexins belong to distinct gene families with no significant sequence homology, though they share key structural features such as four transmembrane domains, intracellular N- and C-termini, and the ability to form aqueous pores approximately 1.5 nm in diameter.^[39] In model organisms like the fruit fly Drosophila melanogaster, at least eight innexin genes have been identified, including Inx1 (also known as ogre), Inx2, Inx3, and Inx7, each contributing to specific tissue channels.^[40] These proteins exhibit a conserved topology that facilitates hexamerization and pore formation, but their extracellular loops differ, influencing docking specificity and channel selectivity.^[41] Innexins are widely distributed across invertebrate tissues, with prominent expression in the nervous system where they form electrical synapses. In the nematode Caenorhabditis elegans, for instance, innexins such as UNC-7 and UNC-9 mediate approximately 10% of neural synapses, facilitating rapid ion flux for synchronized neuronal activity in circuits underlying locomotion and sensory processing.^[42] They are also prevalent in epithelial layers, supporting barrier integrity and coordinated signaling in organs like the gut and gonads.^[43] Recent studies from 2020 to 2025 have illuminated the roles of innexins in invertebrate development and as models for neurodegeneration. In Drosophila, Inx7 gap junctions coordinate projection neuron activity in the antennal lobe, influencing olfactory information processing and circuit maturation during metamorphosis.^[44] Research has also shown that modulation of innexin-based junctions by NMDA receptors enhances olfactory learning by weakening specific connections, highlighting their plasticity in sensory adaptation.^[45] In developmental contexts, innexin genes like Inx2 and Inx7 are essential for axon guidance and epithelial morphogenesis, with disruptions leading to embryonic lethality.^[46] These findings position Drosophila innexin networks as valuable tools for studying neurodegeneration, as altered gap junction coupling mimics synaptic dysfunction in models of neural decline.^[47] Evolutionarily, innexins represent an ancient family predating the divergence of protostomes, while connexins arose later in chordates after the loss of innexin diversity.^[48] Vertebrate pannexins, distant relatives of innexins sharing the four-transmembrane topology, primarily form non-junctional hemichannels rather than intercellular gap junctions.^[49] This separation underscores convergent evolution in channel architecture across phyla.^[50]

Physiological Functions

Electrical and Metabolic Coupling

Gap junctions facilitate electrical coupling between adjacent cells by allowing the direct passage of ions, such as sodium and potassium, through their aqueous pores, enabling the rapid synchronization of action potentials without the need for intermediary neurotransmitters.^[51] This ion flow underlies coordinated electrical activity in excitable tissues; for instance, in the cardiac myocardium, gap junctions formed primarily by connexin43 propagate action potentials at conduction velocities of 0.3–1 m/s, ensuring efficient impulse spread across ventricular muscle.^[52] The strength of this coupling is quantified by the coupling coefficient (Kc), defined as Kc = V2/V1, where V1 is the voltage change in the stimulated cell and V2 is the resulting voltage change in the coupled cell, reflecting the efficiency of electrical signal transfer.^[53] In addition to electrical signaling, gap junctions mediate metabolic coupling by permitting the diffusion of small molecules, including nutrients like glucose and ATP, as well as second messengers such as cyclic AMP (cAMP), which helps maintain cellular homeostasis across coupled cell networks.^[51] This exchange buffers metabolic gradients and supports coordinated responses; for example, in liver hepatocytes, connexin32-containing gap junctions allow cAMP diffusion to regulate glycogenolysis uniformly.^[51] Similarly, in smooth muscle tissues, such as those in the vasculature, gap junctions enable both electrical synchronization for synchronized contractions and metabolic sharing to sustain energy demands during prolonged activity.^[54] Gap junctions also promote coupling in non-excitable cells, as seen in osteocytes within bone, where connexin43 gap junctions allow the propagation of calcium waves and metabolic signals in response to mechanical loading, coordinating osteoblast activity for bone remodeling.^[55] Unlike chemical synapses, which involve unidirectional, vesicle-mediated neurotransmitter release, gap junction-based electrical transmission is bidirectional and non-vesicular, allowing near-instantaneous, reciprocal ion and molecule exchange that enhances network synchrony.^[56]

Independent Hemichannel Roles

Undocked connexons, known as hemichannels, function independently of gap junction formation to mediate paracrine signaling by releasing small molecules such as ATP into the extracellular space. This ATP release acts as a signaling molecule that binds to purinergic receptors on neighboring cells, thereby propagating calcium (Ca²⁺) waves across cell populations. In various tissues, including the inner ear and corneal endothelium, hemichannels formed by connexins like Cx26 and Cx43 facilitate this process, sustaining long-lasting Ca²⁺ signals essential for coordinated cellular responses. Additionally, ATP release through these hemichannels contributes to inflammatory signaling by activating immune responses and promoting the release of pro-inflammatory mediators.^[57]^[58]^[59] In physiological contexts, hemichannels play key roles in environmental sensing and cellular homeostasis. For instance, in osteocytes and osteoblasts, Cx43 hemichannels open in response to mechanical strain, enabling the release of signaling molecules like prostaglandin E2 that drive anabolic bone remodeling and adaptation to physical loading. This mechanosensing function is critical for bone health, as demonstrated in studies showing enhanced bone formation when hemichannel activity is preserved during mechanical stimulation. In astrocytes, hemichannels contribute to volume regulation by allowing the efflux of osmolytes in response to hypoosmotic stress, helping maintain cellular integrity and prevent swelling under fluctuating osmotic conditions. These roles highlight hemichannels' involvement in single-cell responses to mechanical and osmotic cues, distinct from intercellular communication.^[60]^[61]^[62]^[63] Hemichannel gating differs markedly from that of full gap junctions, with undocked hemichannels exhibiting heightened sensitivity to extracellular Ca²⁺ concentrations. Typically, hemichannels remain closed under normal physiological conditions when extracellular Ca²⁺ exceeds 1 mM, preventing unregulated solute leakage, whereas assembled gap junctions maintain openness across a broader range of Ca²⁺ levels. This Ca²⁺-dependent closure is mediated by direct binding to extracellular loops of connexins, inducing conformational changes that stabilize the closed state. Voltage and pH also influence gating, but extracellular Ca²⁺ serves as a primary regulator to ensure hemichannels open only transiently for signaling.^[64]^[65]^[66] Recent advances have focused on therapeutic targeting of hemichannels to mitigate pathological overactivity, particularly using Cx43 mimetic peptides such as Gap19 and Peptide5, which inhibit hemichannel opening by binding to intracellular domains. These peptides have shown promise in preclinical models of stroke, reducing ATP release and Ca²⁺ dysregulation to limit infarct expansion. Unregulated hemichannel overactivity, often triggered by ischemia or inflammation, leads to excessive ATP and glutamate efflux, causing cellular Ca²⁺ overload, osmotic imbalance, and subsequent cell swelling and death. Blocking such activity preserves cellular viability and attenuates tissue damage in these scenarios.^[67]^[68]^[69]^[59]^[68]

Developmental and Tissue-Specific Roles

In Embryonic and Organ Development

Gap junctions play crucial roles in embryonic development by facilitating intercellular communication that coordinates cell proliferation, migration, and differentiation, as well as the diffusion of signaling molecules essential for patterning and organogenesis. In early embryogenesis, connexins such as Cx43 form channels that enable the synchronized behavior of cell populations, ensuring proper tissue formation across various stages. This communication is particularly vital during gastrulation, neurulation, and organ primordia specification, where disruptions lead to developmental anomalies.^[70] Cx43-mediated gap junctions are essential for coordinating cell proliferation and migration in key embryonic processes, including neural tube closure and limb bud formation. In chick embryos, Cx43 expression in the apical ectodermal ridge and underlying mesenchyme supports limb bud outgrowth by maintaining a feedback loop with fibroblast growth factors (FGFs), where downregulation of Cx43 via antisense oligonucleotides results in distal truncations and loss of Fgf-4 and Fgf-8 expression, mimicking apical ridge removal.^[71] Similarly, in mouse neural crest cells derived from the neural tube, Cx43 gap junctions modulate motility through interactions with N-cadherin and p120-catenin, promoting efficient emigration and migration necessary for neural tube closure and subsequent craniofacial development; Cx43 deficiency impairs functional coupling and alters cytoskeletal dynamics without affecting initial expression levels.^[72] Gap junctions also contribute to embryonic patterning by allowing the diffusion of morphogens that establish asymmetries, such as in left-right axis determination. In vertebrate models like Xenopus and chick embryos, connexin-based channels permit the passage of small molecules including cAMP, which acts as a potential morphogen to propagate dorsoventral differences in cell communication, influencing the asymmetric expression of nodal-related genes (e.g., XNR-1) upstream of organ situs decisions; pharmacological blockade or connexin misexpression during stages 5-12 induces heterotaxia by disrupting this signaling.^[73] In organ-specific development, gap junctions are critical for heart septation and lens placode induction. Cx40 and Cx43 co-expression in the developing myocardium supports cardiac looping and outflow tract septation, with combined deficiencies leading to conotruncal malformations and embryonic lethality around E12.5 due to impaired electrical coupling in the conduction system.^[74] For lens formation in mice, Cx43 expression surges specifically in the induced placode cells during head ectoderm thickening, facilitating the intercellular transfer of signals that promote placode invagination and lens vesicle differentiation.^[75] Knockout studies in mice have elucidated these roles, particularly for Cx43. Global Cx43-/- embryos exhibit delayed heart tube looping, pulmonary outflow tract defects, and conotruncal malformations, resulting in perinatal lethality, highlighting Cx43's necessity in myocardial and neural crest-derived septation.^[76] Updated conditional models targeting Cx43 in craniofacial neural crest lineages produce distinct outflow tract anomalies, such as common arterial trunk, without affecting non-crest mesenchyme, confirming region-specific requirements during septation.^[77] These findings underscore metabolic coupling via gap junctions as a mechanism for synchronized proliferation in developing organs. Recent insights emphasize the temporal dynamics of connexin expression in neuronal differentiation. During hippocampal and cortical neurogenesis, connexins like Cx36, Cx45, and Cx43 exhibit stage-specific upregulation.

In Specialized Tissues

In the heart, gap junctions formed primarily by connexin 43 (Cx43) and connexin 40 (Cx40) are essential for coordinating electrical impulse propagation across cardiac tissues. Cx40 predominates in the atria, atrioventricular node, and His-Purkinje system, facilitating rapid conduction from the sinoatrial node to the ventricles, while Cx43 is the main isoform in ventricular myocardium, ensuring synchronized contraction.^[78] Deficiencies in Cx40 lead to slowed conduction velocities, prolonged electrocardiographic intervals (e.g., +46% QS interval in Cx40 knockout mice), and predisposition to arrhythmias such as intra-atrial re-entrant tachycardia and sinoatrial block.^[78] Similarly, disruptions in Cx43 expression or function impair ventricular propagation, contributing to ventricular arrhythmias through uncoupling of cardiomyocytes.^[79] In the ocular lens, gap junctions composed of connexin 46 (Cx46) and connexin 50 (Cx50) maintain cellular homeostasis and optical transparency by enabling the diffusion of ions, metabolites, and second messengers between fiber cells. These connexins form extensive networks that support avascular nutrient transport and waste removal, preventing osmotic imbalances that could scatter light.^[80] Mutations in the genes encoding Cx46 or Cx50, such as the cataract-linked D47A variant in Cx50, disrupt channel assembly or gating, leading to impaired intercellular communication and congenital cataracts characterized by lens opacification.^[80] For instance, Cx50 mutations like S50P inhibit trafficking and function of both homotypic and heterotypic channels with Cx46, exacerbating homeostasis failure.^[81] In neural tissues, particularly the retina, connexin 36 (Cx36) forms gap junctions that promote electrical synchrony among specific neuronal populations, enhancing signal processing. Cx36 gap junctions couple inhibitory interneurons, such as AII amacrine cells in the rod bipolar pathway, allowing averaging of signals to reduce noise and coordinate inhibitory feedback to bipolar and ganglion cells.^[82] In photoreceptors, Cx36 mediates coupling between rod photoreceptors and neighboring cones, enabling rod signals to contribute to cone-mediated vision under mesopic conditions and supporting overall retinal synchrony.^[83] Gap junctions in the uterus, predominantly involving connexin 26 (Cx26), play a critical role in synchronizing myometrial contractions during labor. Cx26 expression increases markedly in human myometrial cells at term, forming intercellular channels that propagate calcium waves and action potentials for coordinated uterine contractions.^[84] This upregulation, alongside connexin 43, transforms the myometrium from a quiescent state to one capable of powerful, synchronized labor contractions.^[84] Recent electrophysiology studies have elucidated the role of Cx36-containing gap junctions in retinal bipolar cells, particularly in type 5A (BC5A) bipolar cells, where they mediate lateral excitatory signaling to refine hierarchical computations in the inner retina. In 2023 experiments using mouse retinas, blocking Cx36 junctions disrupted excitatory inputs to BC5A terminals, altering direction-selective responses in downstream ganglion cells and highlighting their dynamic contribution to visual processing.^[85]

Pathophysiology and Disease Implications

Bystander Effect and Cell Injury

The bystander effect refers to the propagation of cell death signals from a dying cell to adjacent healthy cells through gap junctions, amplifying apoptosis in connected tissues. During apoptosis, gap junction channels remain open, allowing the passage of proapoptotic molecules such as calcium ions (Ca²⁺) and IP₃, triggered by the release of cytochrome c in the dying cell, to neighboring bystander cells, thereby inducing their programmed death.^[86]^[87] This intercellular transfer occurs via direct cytoplasmic coupling, where elevated intracellular Ca²⁺ waves and signals triggered by released cytochrome c lead to caspase activation and mitochondrial dysfunction in recipient cells, as demonstrated in microinjection studies using cytochrome c in various cell lines.^[88] The effect has been observed in vitro, where single-cell induction of apoptosis leads to coordinated death in coupled clusters, highlighting gap junctions' role in synchronizing cell fate decisions.^[89] In scenarios of cell injury and death, such as ischemia in cardiac and neural tissues, gap junction coupling can exacerbate damage by spreading injurious signals, while uncoupling provides protective benefits. During myocardial or cerebral ischemia, open gap junctions facilitate the diffusion of harmful metabolites, ions, and reactive oxygen species between ischemic and viable cells, leading to amplified cell death in the penumbra region.^[90] Conversely, pharmacological or physiological uncoupling of gap junctions prior to or during ischemia reduces infarct size and preserves tissue viability in the heart by limiting signal propagation, as shown in preconditioning models where blockers like heptanol enhance survival.^[91] Similar protective effects occur in the brain, where gap junction blockade mitigates hypoxic-ischemic injury by preventing the spread of excitotoxic signals, underscoring the dual role of coupling in injury amplification versus isolation of damage.^[92]^[93] Gap junctions also contribute to tissue remodeling by coordinating apoptotic death and proliferative responses during wound healing and fibrotic processes. In wound repair, connexin-mediated coupling enables synchronized apoptosis of excess fibroblasts and keratinocytes at the injury site, facilitating scar resolution and epithelial restoration, while promoting proliferation in adjacent regenerative cells through shared growth factors.^[94] This coordination supports matrix remodeling, where coupled fibroblasts exchange signals to balance extracellular matrix deposition and degradation, preventing excessive fibrosis.^[95] In fibrotic remodeling, persistent gap junction communication among myofibroblasts sustains their activation and survival, driving collagen accumulation, though dysregulation can lead to pathological scarring.^[96] The mechanisms underlying these effects involve pH- and Ca²⁺-dependent gating changes in gap junction channels during injury. Acidic extracellular pH, common in ischemic or inflamed tissues, induces chemical gating that partially closes channels, reducing permeability to limit bystander damage spread, as observed in connexin43 (Cx43) channels where protonation alters pore conformation.^[97] Elevated intracellular Ca²⁺ during stress binds to specific residues in the connexin cytoplasmic domains, promoting fast gating and channel closure via electrostatic interactions and calmodulin recruitment, thereby modulating signal propagation.^[98]^[99] These gating dynamics provide a feedback mechanism to isolate injured cells while allowing controlled communication in remodeling contexts. Recent studies highlight the contribution of hemichannels—unapposed gap junction halves—to bystander effects through ATP release in neurodegenerative contexts. In models of neurodegeneration, Cx43 hemichannels open under oxidative stress, releasing ATP that activates purinergic receptors on neighboring cells, propagating inflammatory and excitotoxic signals that amplify neuronal loss.^[100] This hemichannel-mediated ATP efflux, observed in astrocyte-neuron interactions from 2022 to 2025, exacerbates bystander toxicity by sustaining Ca²⁺ dysregulation and microglial activation, distinct from full gap junction roles but synergistic in stress propagation.^[101]^[102]

Associations with Specific Diseases

Mutations in the GJB1 gene encoding connexin 32 (Cx32) are the primary cause of X-linked Charcot-Marie-Tooth disease (CMTX1), the second most common form of Charcot-Marie-Tooth neuropathy, characterized by progressive peripheral nerve demyelination and axonal degeneration leading to muscle weakness and sensory loss. Over 400 distinct mutations have been identified, ranging from missense to frameshift variants, which disrupt Cx32 trafficking, channel function, or oligomerization in Schwann cells, impairing myelin sheath support for axons. These genetic alterations result in a loss-of-function phenotype, with severity varying by mutation type; for instance, extracellular loop mutations often cause more severe central nervous system involvement alongside peripheral symptoms.^[103]^[104] Oculodentodigital dysplasia (ODDD), an autosomal dominant craniofacial disorder with neurological, dental, and ocular manifestations, arises from germline mutations in the GJA1 gene encoding connexin 43 (Cx43). More than 70 mutations, predominantly missense affecting all protein domains, have been linked to ODDD, leading to impaired gap junction formation, altered hemichannel activity, or disrupted trafficking in tissues like skin, brain, and heart. These changes manifest as syndactyly, enamel hypoplasia, microphthalmia, and variable neurological deficits such as spastic paraparesis, highlighting Cx43's role in ectodermal and mesenchymal development. Autosomal recessive forms, rarer, involve compound heterozygous mutations with more severe phenotypes.^[105]^[106] In cancer, Cx43 often functions as a tumor suppressor, with reduced expression correlating to increased malignancy in breast cancer, where Cx43 gap junctions inhibit proliferation and promote apoptosis via intercellular signaling of growth inhibitors. Similarly, Cx43 downregulation in prostate cancer facilitates tumor progression, though some studies indicate elevated Cx43 levels in advanced stages may enhance invasive potential. However, recent analyses reveal Cx43's dual role, acting pro-metastatic in contexts like thyroid and lung cancers by facilitating anoikis resistance and extracellular matrix remodeling through hemichannels and C-terminal interactions. In breast cancer metastasis, Cx43 hemichannels release ATP and metabolites that support tumor cell survival in distant sites, as evidenced in 2024 reviews emphasizing context-dependent functions beyond gap junctions.^[107]^[108]^[109]^[110] Cardiovascular diseases involve dysregulation of Cx43 and Cx40 gap junctions, contributing to arrhythmias and atherosclerosis. In atrial fibrillation, Cx40 mutations or reduced expression impair atrial conduction, promoting re-entrant circuits and heterogeneous repolarization, as shown in 2025 studies on Cx40's role in electrical coupling. Cx43 remodeling, including dephosphorylation and lateralization, exacerbates ventricular arrhythmias post-myocardial infarction by slowing conduction velocity. In atherosclerosis, altered Cx43 and Cx40 expression in endothelial and smooth muscle cells enhances monocyte infiltration and plaque instability; Cx43 overexpression promotes inflammatory signaling, while Cx37 polymorphisms modulate lesion size in human plaques. Recent 2025 research highlights Cx43 phosphorylation states as key regulators of plaque progression.^[111]^[112]^[113]^[114] Neurological disorders link Cx36 and Cx43 alterations to epilepsy, Alzheimer's disease, and stroke. Cx36 gap junctions, predominant in neuronal coupling, show reduced expression in epileptic foci, potentially desynchronizing inhibitory networks and lowering seizure thresholds, though blockade does not consistently suppress seizures in models. In Alzheimer's disease, astrocytic Cx43 hemichannels drive neuroinflammation by releasing ATP and glutamate, exacerbating amyloid-beta toxicity and tau pathology; elevated Cx43 correlates with plaque proximity and cognitive decline in patient brains. Post-stroke, Cx43 hemichannels in astrocytes and neurons propagate excitotoxicity and inflammation during ischemia-reperfusion, with 2020-2025 studies demonstrating neuroprotection via hemichannel inhibition reducing infarct size.^[115]^[116]^[117]^[118]^[119] Therapeutic strategies target gap junction modulation, with rotigaptide enhancing Cx43 coupling to reduce arrhythmia susceptibility in heart failure models by improving conduction and suppressing alternans. Hemichannel blockers like Gap19 and tonabersat mitigate inflammation in neurological and vascular diseases; for instance, Cx43-specific inhibitors attenuate stroke damage by curbing ATP release and bystander propagation of injury signals, while D4 reduces neuroinflammation in epilepsy and Alzheimer's preclinical studies. These agents, progressing to clinical trials, underscore connexin-targeted interventions' potential in disease management.^[120]^[121]^[122]^[68]^[123]

History and Recent Advances

Early Discovery and Characterization

The discovery of gap junctions began with pioneering electron microscopy studies in the mid-20th century, which revealed specialized intercellular contacts in various tissues. In the 1950s, J.D. Robertson's high-resolution electron micrographs of biological membranes, including those in neural and muscle tissues, first highlighted close membrane appositions between adjacent cells, laying the groundwork for identifying discrete junctional structures. By the early 1960s, these observations evolved into detailed descriptions of "nexuses"—tightly fused membrane regions facilitating presumed electrical continuity. Maynard M. Dewey and Lloyd Barr described such nexuses in smooth muscle cells of guinea pig taenia coli in 1962, noting their pentalaminar profile in thin sections and suggesting a role in electrotonic spread of current. Similarly, in 1963, Robertson identified nexuses in goldfish Mauthner cell club endings, observing a hexagonal array of approximately seven-nm subunits in the unit membrane, which implied a structured pathway for intercellular exchange. These findings marked the initial morphological characterization of what would later be recognized as gap junctions. A significant advance in the late 1960s came from freeze-fracture electron microscopy, which exposed intramembrane particles associated with these junctions. In 1968, G.O. Kreutziger provided the first freeze-fracture replicas of mouse liver intercellular junctions, revealing clusters of 7- to 8-nm particles on fracture faces, confirming the particulate nature of nexuses and distinguishing them from other membrane specializations. Concurrently, functional insights emerged from physiological experiments demonstrating metabolic coupling. Werner R. Loewenstein and Yoshio Kanno's 1964 studies on salivary gland cells used intracellular injection of fluorescent dyes like sodium fluorescein, showing rapid diffusion between coupled cells but not across non-junctional membranes, thus evidencing direct cytoplasmic continuity via these structures. These dye-coupling experiments in the 1960s extended to various epithelia and embryonic tissues, establishing that nexuses permitted the passage of small molecules up to about 1,200 Da, beyond mere ionic exchange. The functional significance of these junctions drew parallels to electrical synapses identified in invertebrates, influencing interpretations in vertebrates. Edwin J. Furshpan and David D. Potter's 1959 electrophysiological recordings from crayfish giant motor synapses demonstrated direct electrical transmission without synaptic delay, mediated by low-resistance pathways akin to nexuses. This work, building on earlier observations by Roger W. Sperry on neural connectivity, prompted comparisons to vertebrate tissues, where similar low-resistance coupling was inferred in cardiac and smooth muscle from current spread studies. By the early 1970s, the term "gap junction" was coined to describe these structures, based on precise measurements of a narrow extracellular space (approximately 3-4 nm) between apposed membranes, as revealed by lanthanum staining in electron micrographs of mouse heart and liver by Jean-Paul Revel and Morris J. Karnovsky in 1967. Early characterizations shifted focus from morphology to function, sparking debates on whether gap junctions acted as passive conduits or possessed active regulatory mechanisms. Initial views portrayed them as static low-resistance links for passive ion flow, consistent with electrotonic coupling models. However, Loewenstein's subsequent experiments in the late 1960s and early 1970s revealed dynamic gating, such as voltage- and pH-dependent closure, suggesting active channel-like behavior rather than purely passive diffusion barriers. These findings resolved early controversies, transitioning the field toward understanding gap junctions as regulatable pores integral to cellular coordination.

Molecular Identification and Modern Insights

The molecular identification of gap junction proteins began in the mid-1980s with the cloning of the first connexins, a family of transmembrane proteins that form the core structural units of gap junctions. In 1986, David L. Paul cloned the cDNA for connexin 32 (Cx32), also known as gap junction protein alpha 12, from rat liver, revealing a protein with four transmembrane domains, two extracellular loops, and a cytoplasmic tail, which became the prototype for the connexin family. This was followed in 1987 by Eric C. Beyer and colleagues, who cloned connexin 43 (Cx43) from rat heart, demonstrating sequence homology to Cx32 and establishing the connexin superfamily, with over 20 members identified in vertebrates by the early 1990s based on conserved motifs. These cloning efforts shifted understanding from ultrastructural observations to genetic and biochemical analyses, enabling the recognition that connexins assemble into hexameric connexons that dock to form intercellular channels. In the 1990s, transgenic animal models provided functional validation of connexin roles in vivo, with knockout mice confirming essential functions; for instance, Cx43-null mice exhibited severe cardiac malformations and perinatal lethality, underscoring its necessity for heart development. Concurrently, advances in immunolabeling techniques allowed precise visualization of gap junction plaques, using antibodies against connexins to map their distribution in tissues via immunofluorescence microscopy, revealing dynamic assembly and turnover in epithelial and cardiac cells. The 2000s and 2010s saw refined models of connexin gating and compatibility, integrating biophysical and structural data. Gating mechanisms were elucidated through studies showing voltage-dependent closure of channels in response to transjunctional potential differences, often mediated by the cytoplasmic loop and carboxyl terminus, as detailed in patch-clamp experiments on expressed connexins. Isoform compatibility research demonstrated that not all connexin pairs form functional heterotypic channels; for example, Cx43 can dock with Cx45 but not with Cx62, governed by electrostatic interactions in extracellular loops, informing selectivity in tissue-specific coupling. Recent advances from 2020 to 2025 have leveraged cryo-electron microscopy (cryo-EM) for high-resolution structures, such as the 2021 determination of the Cx43 gap junction at 3.6 Å resolution, revealing pore architecture, lipid interactions, and conformational changes during gating that were previously inferred from lower-resolution models. In 2025, cryo-EM revealed the in situ structure of a gap junction–stomatin complex, providing insights into native assemblies and protein interactions in cellular contexts.^[124] Cx43 has emerged as a target beyond traditional junctions, with studies highlighting its role in cancer progression via non-junctional functions like tumor suppression, as reviewed in a 2024 analysis emphasizing mimetic peptides for modulating glioma invasion. Distinctions from pannexins, which form larger, ATP-releasing channels without direct homologs to connexins, have been clarified, particularly in neuronal contexts where gap junctions enable precise millisecond timing for synchronized firing in inhibitory networks. Evolutionary insights trace connexin origins to primordial innexin-like proteins in early metazoans, with gene duplication events in vertebrates yielding the diverse connexin repertoire, supported by phylogenetic analyses showing shared four-pass transmembrane topology.

References

[1]
https://doi.org/10.1038/sj.jid.5700770
[2]
https://doi.org/10.1134/s1990747821020069
[3]
Gap junctions: structure and function (Review) - PubMed
Gap junctions are plasma membrane spatial microdomains constructed of assemblies of channel proteins called connexins in vertebrates and innexins in ...
[4]
https://doi.org/10.12703/r/11-14
[5]
Gap junctions and the connexin protein family - Oxford Academic
To date, the connexin gene family comprises 20 members in the mouse and 21 members in the human genome, 19 of which can be grouped as sequence-orthologous pairs ...<|separator|>
[6]
Gap Junctions: Basic Structure and Function - ScienceDirect.com
Gap junctions allow the exchange of ions, second messengers, and small metabolites between adjacent cells and are formed by two unrelated protein families, ...
[7]
Connexin - Proteopedia, life in 3D
Feb 6, 2025 · an aqueous pore with a minimum diameter of ∼1.2 nm. When two hemichannels from adjacent cells dock and join, leaving a gap of ∼2–3 nm ...
[8]
Connexin43 phosphorylation in brain, cardiac, endothelial and ...
Reports indicate that Cx43 can be phosphorylated on at least 14 of the 21 serines and 2 of the tyrosines in the cytoplasmic tail region (amino acids 245–382).
[9]
Structure and Functions of Gap Junctions and Their Constituent ...
Gap junction, or nexus, is the conductive type of cell-to-cell contact providing direct transition of small water-soluble molecules with a molecular weight of ...
[10]
Structure and closure of connexin gap junction channels
Apr 17, 2014 · The term “gap” refers to the narrow clearance of 2–4 nm between the two adjoining cells [1]. ... extracellular gap width is 40 Å [32].
[11]
Proteins and Mechanisms Regulating Gap-Junction Assembly ...
Review of posttranslational protein modifications and the binding of protein partners known to regulate GJ biosynthesis, internalization, and degradation.
[12]
Gap junction assembly: roles for the formation plaque and regulation ...
Nov 2, 2011 · First, the apparent delay in assembly in M257 cells can logically be interpreted as a suppressed trafficking to the plasma membrane and/or to ...
[13]
Dynamic trafficking and delivery of connexons to the plasma ... - PNAS
We found that connexons exit the Golgi region predominantly in vesicular carriers that traffic along MTs to reach the PM. Post-Golgi trafficking along MTs and ...Results · Gj Channel Clusters Grow By... · Connexons Traffic In...<|separator|>
[14]
Gap Junctions Revealed by Freeze-Fracture Electron Microscopy
These studies have revealed gap junction structure to consist of plaque-like approximations of closely apposed plasma membranes. The space between cells sharing ...
[15]
https://doi.org/10.1152/ajpcell.00316.2010
[16]
https://doi.org/10.1529/biophysj.103.036350
[17]
https://doi.org/10.1016/0896-6273(91)90128-m
[18]
https://doi.org/10.1038/317331a0
[19]
https://doi.org/10.1016/j.bbamem.2004.01.008
[20]
Gating of mammalian cardiac gap junction channels by ... - PubMed
The normalized steady-state junctional conductance-voltage relationship (Gss-Vj) was a bell-shaped curve that could be adequately described by a two-state ...
[21]
Gap Junction Intercellular Communication: A Review of a Potential ...
GAP JUNCTIONS AND BONE. Gap junctions are present in all types of vertebrate cells, with the few exceptions of red blood cells, platelets, and some neurons ...
[22]
Diversity in connexin biology - PMC - NIH
Note that Cx43, Cx26, and Cx32 are the three most widely distributed connexin isoforms being found in numerous human organs. The vast majority of the 33 human ...
[23]
Remodelling of gap junctions and connexin expression in diseased ...
Three principal connexins are expressed in cardiac myocytes, connexin43 (Cx43), Cx40, and Cx45. Although Cx43 predominates in the heart as a whole, it is ...
[24]
Channeling Diversity: Gap Junction Expression in the Heart - PMC
Jul 1, 2013 · There are at least five different connexins expressed in the adult mammalian heart (Table I). These include members of the alpha (Cx43 and Cx40) ...
[25]
Connexin40 and Connexin43 Determine Gating Properties of Atrial ...
The principal purpose of this investigation was to assess quantitatively the contributions of Cx40 and Cx43 to the total atrial gj and to determine how connexin ...
[26]
marked enhancement of liver function in a hepatoma cell line
In vivo, normal rodent hepatocytes express Cx32 and Cx26, but only Cx32 expression is constant across the liver lobule [6]. Thus, liver gap junction ...
[27]
The Liver Connexin32 Interactome Is a Novel Plasma Membrane ...
Apr 16, 2013 · (12) Loss of Cx32 (or depletion from the plasma membrane) enhances tumorigenesis in liver.
[28]
Regulation of connexin32 and connexin43 gene expression by DNA ...
These results suggest that transcription of Cx32 and Cx43 in hepatic cells is controlled by promoter methylation and by cell-specific transcription factors.
[29]
Expression of Cx36 in mammalian neurons - PubMed
In the present review we summarize the evidence in favour of its predominant expression in neuronal cells in the mammalian central nervous system.
[30]
Expression of Cx36 in mammalian neurons - ScienceDirect.com
Cx36 is predominantly expressed in neuronal cells of the mammalian central nervous system, including the inferior olive and hippocampus.
[31]
Connexin 43 Expression Reflects Neural Crest Patterns during ...
Apr 15, 1999 · We used transgenic mice in which the promoter sequence for connexin 43 linked to a lacZ reporter was expressed in neural crest but not myocardial cells.
[32]
Gap junction protein Connexin-43 is a direct transcriptional regulator ...
Sep 21, 2018 · We show that Connexin 43 (Cx43) controls neural crest cell migration in vivo by directly regulating N-cadherin transcription.
[33]
Connexinplexity: the spatial and temporal expression of connexin ...
A gap junction connexin is required in the vertebrate left–right organizer. ... gap junction channels in model systems and native tissues. FEBS Lett. 2014 ...
[34]
Photoreceptor Coupling Is Controlled by Connexin 35 ...
We examined the molecular mechanism that controls photoreceptor coupling in zebrafish retina. Connexin 35 (homologous to Cx36 of mammals) was found at both cone ...Missing: variations | Show results with:variations
[35]
Cloning and Expression of Two Related Connexins from the Perch ...
Oct 1, 1998 · Screening for connexins in this species has yielded two connexins closely related to Cx35 that are expressed primarily in retina and brain.Missing: variations | Show results with:variations
[36]
Connexinplexity: the spatial and temporal expression of connexin ...
Our analysis has identified new patterns for well-known connexins and assigned spatial and temporal expression to genes with no-existing information.
[37]
Differential Expression of Connexins during Neocortical ...
We found that these connexins (Cxs) are expressed differentially during development, and their patterns of expression are correlated with important ...
[38]
Innexins: a family of invertebrate gap-junction proteins - PMC
We propose the name innexins (invertebrate analogues of the connexins) for invertebrate gap-junction proteins.
[39]
Innexins: members of an evolutionarily conserved family of gap ...
Innexins were originally characterized as the structural components of gap junctions in Drosophila, an arthropod, and the nematode Caenorhabditis elegans.
[40]
A structural and functional comparison of gap junction channels ...
Gap junctions are dense arrays of hundreds or thousands of intercellular channels in regions where cell membranes are closely apposed. The earliest structural ...
[41]
Gene expression pattern Gap junctions in Drosophila
Invertebrate gap junctions are composed of proteins called innexins and eight innexin encoding loci have been identified in the now complete genome sequence ...
[42]
(PDF) A Structural and Functional Comparison of Gap Junction ...
Aug 6, 2025 · Despite a lack of similarity in gene sequence, connexins and innexins are remarkably similar. Innexins and connexins have the same membrane ...
[43]
Interactions between innexins UNC-7 and UNC-9 mediate electrical ...
Approximately 10% of Caenorhabditis elegans nervous system synapses are electrical, that is, gap junctions composed of innexins. The locomotory nervous system ...
[44]
Innexins: Expression, Regulation, and Functions - Frontiers
Oct 10, 2018 · The innexin (Inx) proteins form gap junction channels and non-junctional channels (named hemichannels) in invertebrates.
[45]
The Innexin 7 gap junction protein contributes to synchronized ...
Jan 20, 2025 · Here we focus on the functional role that Inx7 plays in Drosophila olfactory function. Our data demonstrate that knock-down of Inx7 in AL ...Missing: Inx1- | Show results with:Inx1-
[46]
NMDAR-mediated modulation of gap junction circuit regulates ...
Jul 10, 2020 · We show that modulation of the gap junctions facilitates olfactory learning. Learning experience weakens the gap junctions and induces a repulsive sensory ...
[47]
The Drosophila innexin 7 gap junction protein is required ... - PubMed
The results suggest an essential role for innexin7 for axon guidance and embryonic nervous system development in Drosophila.Missing: Inx1- | Show results with:Inx1-
[48]
Wrapping glia regulates neuronal signaling speed and precision in ...
Sep 8, 2020 · Here, we addressed whether gap junctional coupling is required for wrapping glial growth. Drosophila gap junctions are generated by innexins.
[49]
Connexins evolved after early chordates lost innexin diversity - eLife
Jan 19, 2022 · Non-chordates use the primordial innexins, while chordates use connexins that superseded the gap junction function of innexins.
[50]
Are there gap junctions without connexins or pannexins?
Feb 26, 2019 · Two unrelated protein families are currently considered to be involved in this function, namely, connexins and pannexins (pannexins/innexins).Missing: analogues | Show results with:analogues
[51]
Evolutionary analyses of gap junction protein families - ScienceDirect
Although all pannexins and connexins are packed into hexamers forming single channels, only non-chordate pannexins (innexins) and connexins form gap junctions.
[52]
Gap Junctions - PMC - PubMed Central - NIH
Connexins can show a remarkably rapid turnover rate for a membrane protein. For example, the in vivo half-life of Cx32 in gap junctional plaques from rodent ...
[53]
Role of gap junctions in the propagation of the cardiac action potential
Critical gap junctional uncoupling reduces conduction velocities to a much larger extent than does a reduction of excitability, which suggests that the safety ...
[54]
Cellular composition and circuit organization of the locus coeruleus ...
The coupling coefficient from cell 1 to cell 2 (CC1) was defined as V2/V1 and the coupling coefficient in the opposite direction from cell 2 to cell 1 (CC2) ...
[55]
Electrophysiology of Syncytial Smooth Muscle - PMC
Jan 17, 2019 · The coupling is mediated by cell-to-cell communication pathways known as gap junctions, which constitute electrical pathways of high conductance ...Passive Electrical... · Action Potentials · Recent Developments
[56]
Gap Junctions and Biophysical Regulation of Bone Cells - PMC - NIH
In this review, we demonstrate the integral role of gap junctional intercellular communication (GJIC) in skeletal physiology and bone cell mechanosensing.
[57]
Synchrony and So Much More: Diverse Roles for Electrical ...
Unlike chemical synapses, the large majority of electrical synapses conduct bidirectionally. This is especially true in vertebrate systems. If input patterns ...
[58]
ATP release through connexin hemichannels and gap ... - PNAS
Dec 2, 2008 · Our results demonstrate that these connexins play a dual crucial role in inner ear Ca 2+ signaling: as hemichannels, they promote ATP release, sustaining long- ...
[59]
Connexin Hemichannels and Gap Junction Channels Are ...
Understanding the Role of ATP Release ... ATP Release Via Connexin Hemichannels Controls Intercellular Propagation of Ca2+ Waves in Corneal Endothelial Cells.
[60]
Connexin 43 hemichannels and related diseases - PMC
Nov 11, 2024 · These data suggest that ATP release mediated by Cx43 hemichannels likely plays a significant, detrimental role in inflammatory responses, neural ...
[61]
Mechanical Strain Opens Connexin 43 Hemichannels in Osteocytes
Hemichannels are regulated by extracellular Ca2+, and these Ca2+ regulated hemichannels control the osmotic volume of the cell (Quist et al., 2000; Gomez- ...
[62]
Connexin hemichannels with prostaglandin release in anabolic ...
Feb 8, 2022 · This study documents a key role for osteocyte-derived Cx43 hemichannels in the anabolic response of bone to mechanical stimulation.
[63]
Connexin Hemichannels in Astrocytes: Role in CNS Disorders
Feb 5, 2019 · Unpaired connexins can act as hemichannels, which are responsible for the release of gliotransmitters, including ATP, glutamate, nicotinamide ...Missing: mechanosensing osteoblasts
[64]
Physiological Role of Gap-Junctional Hemichannels
We conclude that nongap-junctional hemichannels regulate cell volume in response to the change in extracellular physiological calcium in an otherwise isosmotic ...
[65]
Mechanism of gating by calcium in connexin hemichannels - PMC
Nov 21, 2016 · To maintain an adequate permeability barrier, hemichannels are tightly regulated by normal extracellular Ca2+ to be closed under most conditions ...
[66]
Calcium Regulation of Connexin Hemichannels - MDPI
ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca2+ signals across the inner ear. Proc. Natl. Acad. Sci ...
[67]
Molecular basis of calcium regulation in connexin-32 hemichannels
Most hemichannels are activated by depolarization, and opening depends critically on the external Ca2+ concentration. Here we describe the mechanisms of action ...
[68]
Connexin 43 hemichannels and related diseases - Oxford Academic
Nov 11, 2024 · Cx43 hemichannels have emerged as potential therapeutic targets in various diseases, including central nervous system disorders, bone-related ...
[69]
Over-activated hemichannels: A possible therapeutic target for ...
In this review, we summarize recent findings in the field of hemichannel modulation via specific tools, and how these tools could improve patient outcome.
[70]
Peptidic Connexin43 Therapeutics in Cardiac Reparative Medicine
In this review, we survey preclinical and clinical data available on short mimetic peptides based on, or directly targeting, Cx43, with focus on their potential ...
[71]
Connexins and Pannexins: Important Players in Neurodevelopment ...
Cxs and Panxs play an important role in early stages of neuronal development with a wide span of action ranging from cellular migration during early stages to ...
[72]
https://doi.org/10.1083/jcb.200106109
[73]
Reduced cardiac conduction velocity and predisposition to ...
Our results demonstrate the function of Cx40 in the regulation and coordination of heart contraction and show that cardiac arrhythmogenesis can not only be ...
[74]
Cardiac connexins and impulse propagation - ScienceDirect.com
Abnormal Cx40 expression is associated with atrial fibrillation, while abnormal Cx43 expression in the ventricle is associated with ventricular arrhythmias.
[75]
Cataract-associated connexin 46 mutation alters its interaction with ...
The lens is an avascular organ and thus relies in part upon gap junction channels and hemichannels to maintain its metabolic homeostasis and transparency.
[76]
The cataract causing Cx50-S50P mutant inhibits Cx43 and ...
Apr 1, 2009 · Mutations in Connexin50 (Cx50) cause cataracts in both humans and mice. The mechanism(s) behind how mutated connexins lead to a variety of ...
[77]
Article The Synaptic and Circuit Mechanisms Underlying a Change ...
Apr 16, 2014 · These experiments were conducted using retinas from wild-type (WT) and Cx36−/− mice, in which gap junctions in both the inner and outer retina ...
[78]
Connexin36 Is Essential for Transmission of Rod-Mediated Visual ...
Gap junctions are composed of intercellular channels that span the plasma membranes of adjacent cells, thereby coupling them with a low-resistance electrical ...
[79]
Connexin-26 and connexin-43 are differentially expressed and ...
Gap junctions are characteristically increased in the myometrium during term and preterm delivery and are thought to be essential for the development of labor ...
[80]
Hierarchical retinal computations rely on hybrid chemical-electrical ...
Feb 28, 2023 · These results indicate that CX36-containing gap junctions mediate lateral excitatory signals to BC5A terminals.
[81]
Gap junctions remain open during cytochrome c-induced cell death
Feb 17, 2006 · Clearly, proapoptotic factors such as Ca2+ and reactive oxygen species can readily pass through gap junction channels to exert their effects on ...
[82]
Mitochondrial apoptosis is amplified through gap junctions - PMC
The bystander effect induced by cytochrome c microinjection was also assessed in UMR cells to further explore the role of gap junctions. UMR and MG63 are ...
[83]
Critical role of gap junction communication, calcium and nitric oxide ...
Apr 30, 2015 · Single-cell microinjection of cytochrome c can result in gap junction-mediated apoptotic cell death of bystander cells in head and neck cancer.
[84]
The spread of apoptosis through gap-junctional channels in BHK ...
An in vitro system was used to explore the transmission of death signals from apoptotic cells to cells with which they were coupled via gap junctions.
[85]
Gap junction-mediated spread of cell injury and death during ...
GJ play an important role in the pathphysiology of cell injury and death during myocardial ischemia–reperfusion and are potential targets for new ...
[86]
Gap junction uncoupling protects the heart against ischemia
Conclusion: Directly blocking gap junctions preconditions the heart. This protection is not a direct result of a decrease in developed pressure before a ...
[87]
Blockade of Gap Junctions In Vivo Provides Neuroprotection After ...
Conclusions—Gap junction blockade may be a useful therapeutic tool to minimize brain damage produced by perinatal and early postnatal HI. (Stroke. 2005;36:2232- ...
[88]
Ischemia-Induced Brain Damage Depends on Specific Gap ...
Because gap junctions directly connect the cytoplasms of coupled cells, they offer a way to propagate stress signals from cell to cell. The authors investigated ...
[89]
Gap junctional communication in tissue inflammation and repair
Remodeling of the connective tissue occurs at final stages of wound healing, a process that is tightly regulated by a balance between cell proliferation and ...
[90]
Normal and Pathologic Soft Tissue Remodeling: Role of the ... - Nature
Dec 1, 2003 · Gap junctions between cells also allow communication between adjacent myofibroblasts. ... Later in wound healing as remodeling occurs, it is ...
[91]
https://www.sciencedirect.com/science/article/pii/S0022522302000892
[92]
Gap junction channel gating - ScienceDirect.com
Low pH closes most GJ channels and may serve as a mechanism to limit the spread of injury from damaged to normal tissue. It was shown that low pH produces ...
[93]
An electrostatic mechanism for Ca2+-mediated regulation of gap ...
Jan 12, 2016 · Gap junction channels mediate intercellular signalling that is crucial in tissue development, homeostasis and pathologic states such as ...
[94]
Chemical gating of gap junction channels: Roles of calcium, pH and ...
While it is clear that Ca2+ affects channel gating, the [Ca2+]i that activates the gating mechanism is still uncertain, and may vary among connexins and cell ...
[95]
Cx43 hemichannels contribute to astrocyte-mediated toxicity ... - PNAS
(J) Supernatant ATP of FALS hiPSC-A is significantly higher than control. ... neurodegeneration. We utilized our hiPSC-based platform to examine whether ...Cx43 Hemichannels Contribute... · Results · The Cx43 Hc Blocker...
[96]
Connexins and Pannexins: Important Players in Neurodevelopment ...
Cx43 is expressed from the embryonic to the adult stage and is highly expressed in the hippocampus and cerebellum. Cx30 expression, on the other hand, begins ...
[97]
Connexin and Pannexin Hemichannels: Broad‐Spectrum Players in ...
Sep 16, 2025 · This signaling escalates ATP and glutamate release and likely other neurotoxic factors, driving neurodegeneration (Takeuchi et al. 2006; ...
[98]
Connexin32 Mutations Associated with X-Linked Charcot–Marie ...
The X-linked form of Charcot–Marie–Tooth disease (CMTX) is associated with mutations in the gene encoding connexin32 (Cx32), which is expressed in Schwann ...
[99]
GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X ... - NCBI
Jun 18, 1998 · Central nervous system involvement in four patients with Charcot-Marie-Tooth disease with connexin 32 extracellular mutations. J Neurol ...
[100]
Syndromic and non-syndromic disease-linked Cx43 mutations
Apr 17, 2014 · This review focuses on the links between germ-line mutations in the gene encoding Cx43 (GJA1) and the human disease termed oculodentodigital ...
[101]
Oculo-dento-digital dysplasia: a systematic analysis of published ...
Mar 29, 2023 · In 2003, ODDD became known as the first human disease to be linked to germline Cx43 gene (GJA1) mutations [4]. Cx43 is one of the 20 members of ...
[102]
Deficiency of Connexin43 Gap Junctions Is an Independent Marker ...
In summary, this study provides evidence of decreased expression of Cx43 gap junctions in breast cancer at various stages of progression as well as breast ...
[103]
Connexin 43, breast cancer tumor suppressor: Missed connections?
Apr 28, 2016 · This review highlights the most abundant gap junction connexin isoform in higher vertebrate organisms, Connexin 43, and its role in breast ...
[104]
Connexin 43 expression is associated with increased malignancy in ...
May 10, 2015 · These data suggest that Cx43 is associated with increased malignancy and progression in prostate cancer cells. Pharmacological manipulation of ...
[105]
Connexin-43 in Cancer: Above and Beyond Gap Junctions! - PMC
Recent studies suggested that Cx43 might facilitate cancer cell survival by mediating anti-apoptotic and growth signals via gap junctions, as well as promote ...
[106]
Connexin 40 in atrial fibrillation: pathophysiological roles and ...
Oct 28, 2025 · Among cardiac connexins, Cx40, Cx43, and Cx45 constitute the major subtypes that form gap junctions (GJs), facilitating rapid electrical signal ...
[107]
Research progress of connexin 43 in cardiovascular diseases
This review summarizes the role of Cx43 in cardiac diseases, explores its functional changes under electrophysiological and pathological conditions, and ...Missing: Cx40 | Show results with:Cx40
[108]
Connexin 43 across the Vasculature: Gap Junctions and Beyond
Cx43 is expressed in conduit vessels, but this expression is variable based on location, tissue size, and disease state. Cx43 in Conduit Vessel EC. Cx40 and, to ...
[109]
Connexins in atherosclerosis - ScienceDirect.com
Three main connexins are expressed in cells involved in atherosclerosis: Cx37, Cx40 and Cx43. Cx37 is found in endothelial cells, monocytes/macrophages and ...
[110]
Effects of Constitutive and Acute Connexin 36 Deficiency on Brain ...
To understand the reciprocal interactions between Cx36 and seizure-like neural activity, we examined three questions: (a) does Cx36 deficiency affect seizure ...Abstract · Introduction · Results · Discussion
[111]
Research progress of connexins in epileptogensis
Mar 15, 2025 · However, blocking connexin 36 (Cx36) with quinine did not stop seizure-like events, which persisted in 7 out of 11 slices. These findings ...
[112]
Astrocytic Connexin43 in Alzheimer's disease - PubMed
This review provides a comprehensive summary of the pathophysiological roles of Cx43 in AD, with emphasis on its hemichannel function, and the interaction ...
[113]
Connexin43 Contributes to Alzheimer's Disease by Promoting the ...
Oct 23, 2024 · Studies have shown that Cx43 activity is significantly increased in the postmortem AD brains and AD model mice [28], which subsequently reduces ...
[114]
The Multifaceted Role of Astrocyte Connexin 43 in Ischemic Stroke ...
More importantly, astrocytic gap junction channels also transmit chemical signals and metabolites (glucose and lactate) between glial cells, facilitating the ...
[115]
Gap junction modifier rotigaptide decreases the ... - PubMed
Gap junction modifier rotigaptide decreases the susceptibility to ventricular arrhythmia by enhancing conduction velocity and suppressing discordant alternans ...
[116]
Rotigaptide Infusion for the First 7 Days After Myocardial Infarction ...
Apr 17, 2021 · Early gap junction enhancement reduces late complexity of infarct scar. ... These changes can be identified using magnetic resonance indices. What ...
[117]
Connexin therapeutics: blocking connexin hemichannel pores is ...
Sep 22, 2020 · Compounds that block the function of connexin and pannexin protein channels have been suggested to be valuable therapeutics for a range of diseases.
[118]
The connexin hemichannel inhibitor D4 produces rapid ...
Aug 20, 2023 · We found that blocking mainly Cx hemichannels with D4 produces antidepressant-like effects by suppressing neuroinflammation. Methods. Animals.