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Calcium-binding protein

Calcium-binding proteins are a diverse superfamily of proteins that selectively bind calcium ions (Ca²⁺) through specialized motifs, primarily the EF-hand helix-loop-helix structure, enabling them to function as intracellular calcium sensors, buffers, and regulators of cellular signaling pathways.^[1] These proteins undergo conformational changes upon calcium binding, which allows them to interact with and modulate target molecules such as enzymes, ion channels, and cytoskeletal elements, thereby transducing calcium signals into specific biological responses.^[2] Found across all domains of life but particularly abundant in eukaryotes, calcium-binding proteins play essential roles in fundamental processes including muscle contraction, neurotransmitter release, gene expression, cell proliferation, differentiation, and apoptosis.^[3] Notable members include calmodulin, a ubiquitous sensor that regulates over 300 targets like kinases and phosphatases; troponin C, critical for cardiac and skeletal muscle function; parvalbumin, involved in neuronal fast-spiking activity; and S100 proteins, which contribute to inflammation and cancer progression.^[4] Dysregulation of these proteins is implicated in various diseases, such as neurological disorders (e.g., via calbindin mutations), cardiac arrhythmias (e.g., troponin defects), and cancers (e.g., S100 overexpression).^[2] Their structural diversity—ranging from compact EF-hand domains in calmodulin-like proteins to more disordered, high-capacity binding in proteins like calsequestrin—underpins their versatility in maintaining calcium homeostasis across a steep intracellular-extracellular gradient of 20,000- to 100,000-fold.^[3]

Fundamentals

Definition and Properties

Calcium-binding proteins are a diverse class of proteins that selectively bind Ca²⁺ ions through coordination sites optimized for this divalent cation, enabling them to regulate intracellular Ca²⁺ homeostasis and act as intermediaries in Ca²⁺-dependent processes.^[5]^[3] Unlike general metal-binding proteins, they exhibit coordination geometries that prioritize Ca²⁺ due to its larger ionic radius and flexible hydration shell, distinguishing them from binders of smaller ions like Zn²⁺ or Fe²⁺.^[3] These proteins typically display high affinity for Ca²⁺, with dissociation constants (K_d) ranging from 10⁻⁶ to 10⁻⁸ M, which aligns with the physiological range of cytosolic Ca²⁺ fluctuations from resting levels below 100 nM to signaling peaks in the micromolar range.^[6]^[7] This affinity is coupled with marked specificity over Mg²⁺, the most abundant intracellular divalent cation, as Mg²⁺ binding is weaker (K_d ≈ 10⁻³ M) owing to its tighter hydration and smaller size, preventing competitive interference under normal conditions.^[6]^[3] Calcium-binding proteins are prevalent in eukaryotes, with over 700 such proteins annotated in the human proteome, reflecting their broad distribution across cellular compartments and diverse gene families.^[8] Their properties facilitate the maintenance of low basal cytosolic free Ca²⁺ concentrations (∼100 nM) to avoid cellular toxicity while permitting rapid, localized increases for regulatory purposes.^[7]

Biological Importance

Calcium-binding proteins play a central role in cellular calcium homeostasis by buffering intracellular Ca²⁺ concentrations, maintaining cytosolic levels at approximately 100 nM to prevent toxicity from excess free Ca²⁺, which could otherwise lead to precipitation of calcium phosphate salts or activation of destructive enzymes like proteases and nucleases.^[9] These proteins facilitate rapid Ca²⁺ signaling by binding and releasing ions in response to transient elevations, enabling precise control over physiological responses without sustained overload.^[10] Structural motifs such as EF-hands allow this dynamic regulation, ensuring Ca²⁺ serves as an effective second messenger.^[9] These proteins exhibit remarkable evolutionary conservation across eukaryotes, with core components of the Ca²⁺ signaling toolkit, including EF-hand domains, present in the last eukaryotic common ancestor and diversified through gene duplication over billions of years.^[11] This conservation underscores their foundational role in eukaryotic cellular complexity, particularly in the transition to multicellularity, where expanded Ca²⁺-binding protein diversity supported coordinated development and intercellular signaling in metazoans.^[11] Dysregulation of calcium-binding proteins disrupts these homeostatic and signaling functions, contributing to diseases such as neurodegeneration and cancer through altered Ca²⁺ dynamics.^[10] In neurodegeneration, mutations in proteins like MICU1 impair mitochondrial Ca²⁺ uptake, leading to neuronal vulnerability and conditions like myopathy-associated neurodegeneration.^[10] Similarly, aberrant expression of S100 family proteins promotes oncogenic signaling and tumor progression in cancers like melanoma.^[9]

Structural Features

Binding Motifs

Calcium-binding proteins employ diverse structural motifs to coordinate Ca²⁺ ions with high specificity and affinity, enabling their roles in cellular regulation. These motifs typically involve oxygen-containing side chains from amino acids such as aspartate (Asp) and glutamate (Glu), along with backbone carbonyl groups, to form coordination complexes that stabilize the protein's interaction with calcium. The architecture of these motifs varies, reflecting adaptations to different physiological contexts, but all prioritize efficient chelation of the Ca²⁺ ion's coordination sphere.^[1] The EF-hand motif, first identified in the crystal structure of carp parvalbumin, represents one of the most prevalent calcium-binding architectures. It consists of a helix-loop-helix structure, where a 12-residue loop connects two alpha helices, coordinating the Ca²⁺ ion via seven oxygen atoms in a pentagonal bipyramidal geometry. These ligands include side-chain carboxylates from Asp or Glu residues at key positions (typically 1, 3, and 12 in the loop), a side-chain oxygen from serine or threonine at position 5, and backbone carbonyl oxygens at positions 9 and 7, with Ca-O bond lengths averaging approximately 2.4 Å. The canonical sequence pattern of the loop is often denoted as DXDXVG...DE, where D represents Asp, X is any residue (commonly Asp or Asn), V is valine or isoleucine, G is glycine, and E is Glu, facilitating the precise positioning of coordinating groups.^[12]^[13]^[14] Another prominent motif is the C2 domain, a compact β-sandwich fold of about 130 residues that binds two to three Ca²⁺ ions through three flexible loops at the C-terminal end of the structure. These loops, rich in Asp residues, form a bipartite or tripartite binding site that enhances membrane association in response to elevated Ca²⁺ levels, commonly observed in signaling proteins like protein kinase C isoforms. The domain's β-sheet topology positions the loops to interact with phospholipid headgroups, with Ca²⁺ coordination involving five to eight oxygen atoms per site, adapting the protein's affinity for lipids.^[15]^[16] Additional motifs include the annexin repeat, characterized by a curved, helical core within each of four or eight repeats that houses multiple Ca²⁺-binding sites on the concave surface. These sites, often type II or III configurations, utilize a GxGT...D/E sequence pattern where backbone amides and side-chain carboxylates from Glu or Asp coordinate Ca²⁺, promoting phospholipid binding in a calcium-dependent manner. In vitamin K-dependent proteins, the γ-carboxyglutamic acid (Gla) domain features 9–12 post-translationally modified Gla residues that chelate Ca²⁺ via their bis-carboxylate groups, forming an extended network that tethers the protein to membranes, as exemplified in coagulation factors like prothrombin.^[17]^[18]

Conformational Dynamics

Calcium-binding proteins, particularly those featuring the EF-hand motif, exhibit allosteric transitions triggered by Ca²⁺ binding that fundamentally alter their structure to facilitate downstream interactions. In the apo form, the two α-helices flanking the binding loop are oriented in a closed conformation, shielding a hydrophobic patch within the protein core. Upon Ca²⁺ coordination, the loop adopts a more extended geometry, causing the helices to splay outward—often likened to calipers opening—and exposing this hydrophobic surface for transient protein-protein associations essential to signaling cascades.^[1]^[19] Affinity modulation in these proteins arises from cooperative binding across multiple sites, where occupation of one Ca²⁺ site enhances affinity at adjacent sites through interdomain communication. This cooperativity is quantified by Hill coefficients greater than 1, reflecting positive allostery; in multi-site or tetrameric configurations, coefficients can reach up to 4, indicating strong synergistic effects that sharpen the response to Ca²⁺ concentration changes.^[19] Spectroscopic techniques provide direct evidence of these dynamics, revealing shifts from flexible to more ordered states upon Ca²⁺ saturation. Nuclear magnetic resonance (NMR) spectroscopy demonstrates high loop flexibility in the Ca²⁺-free state, with disorder in the binding regions allowing rapid conformational sampling, whereas binding induces stabilization and reduced motional amplitudes in these loops.^[20] Complementarily, X-ray crystallography captures helix rigidification post-binding, where the ingress of Ca²⁺ ions aligns the coordinating residues, transitioning the EF-hand from a dynamic, closed scaffold to a rigid, open architecture that propagates allosteric signals.^[14]

Classification

EF-Hand Proteins

EF-hand proteins constitute the largest superfamily of calcium-binding proteins, comprising over 200 genes in the human genome that encode proteins containing at least one EF-hand domain.^[21] This superfamily is subdivided into numerous subfamilies, including the calmodulin-like subfamily (e.g., calmodulin and troponin C, typically with four EF-hands), the parvalbumin-like subfamily (e.g., parvalbumin and oncomodulin, often with three EF-hands), and the S100 subfamily (with around 24 genes in humans encoding proteins that form homodimers or heterodimers).^[22] These subfamilies exhibit functional diversity while sharing the core EF-hand motif, a helix-loop-helix structure that coordinates calcium ions with high affinity.^[23] Structurally, EF-hand motifs in these proteins are predominantly organized in pairs, where two EF-hands form compact globular domains known as EF-lobes, enhancing stability and cooperative calcium binding.^[24] In many cases, these paired motifs assemble into larger multi-domain architectures, such as the four-EF-hand globular structures in calmodulin-like proteins, which allow for sequential conformational changes upon calcium binding. Some members, particularly in the S100 subfamily, incorporate pseudo-EF-hands—modified loops with 14 amino acids instead of the canonical 12—that do not bind calcium but contribute to structural integrity and dimerization.^[25] This diversity in pairing and domain organization enables varied calcium-sensing capabilities across the superfamily. Evolutionarily, the EF-hand superfamily originated in early eukaryotes from a primordial single EF-lobe precursor, with subsequent gene duplications and fusions driving expansion and specialization.^[22] For instance, the calmodulin-like and parvalbumin-like subfamilies arose through tandem duplications of an ancestral four-domain unit, leading to tissue-specific adaptations such as high-affinity buffering in parvalbumin.^[26] The S100 subfamily further diversified via chromosomal clustering and additional duplications, particularly on human chromosome 1q21, facilitating specialized roles in inflammation and cell proliferation.^[22] These evolutionary events underscore the superfamily's adaptability in eukaryotic calcium signaling networks.

Non-EF-Hand Proteins

Non-EF-hand calcium-binding proteins employ diverse structural motifs to coordinate Ca²⁺ ions, enabling their roles in cellular processes distinct from the canonical helix-loop-helix architecture of EF-hands. These proteins often feature repeat domains or specialized folds that facilitate Ca²⁺-dependent interactions with membranes, lipids, or other molecules, and they are found in both intracellular and extracellular environments.^[27] The annexin family exemplifies non-EF-hand calcium-binding proteins, comprising 12 members in humans (ANXA1–ANXA11 and ANXA13) that bind phospholipids in a Ca²⁺-dependent manner. Each annexin consists of a core domain with 4–8 homologous repeats of approximately 70 amino acids, forming a compact, α-helical structure that generates a concave surface for Ca²⁺ coordination and subsequent phospholipid binding. These repeats contain type II and III Ca²⁺-binding sites, where Ca²⁺ ions bridge the protein to negatively charged membrane lipids, promoting membrane association at elevated Ca²⁺ concentrations.^[17]^[28]^[29] C2 domain-containing proteins represent another major class of non-EF-hand Ca²⁺ binders, prominently including synaptotagmins and copines, which mediate Ca²⁺-triggered membrane interactions. The C2 domain, a compact β-sandwich fold of about 130 residues, typically coordinates 1–3 Ca²⁺ ions per domain through aspartate-rich loops, inducing a conformational shift that inserts hydrophobic residues into lipid bilayers for docking. In synaptotagmins, such as synaptotagmin I, tandem C2A and C2B domains enable rapid Ca²⁺ sensing and synaptic vesicle fusion, while copines, with their single or dual C2 domains, similarly exhibit Ca²⁺-dependent phospholipid affinity for vesicular trafficking.^[30]^[31]^[32] Other notable non-EF-hand proteins include intracellular examples like calreticulin, which adopts a lectin-like fold for Ca²⁺ storage in the endoplasmic reticulum, and extracellular secretory phosphoproteins such as caseins. Calreticulin features an N-terminal globular lectin domain for glycoprotein recognition and a C-terminal tail rich in charged residues that provides high-capacity, low-affinity Ca²⁺ binding, buffering up to 1–25 Ca²⁺ ions per molecule to maintain ER Ca²⁺ homeostasis. In contrast, caseins, major components of milk micelles, utilize clusters of phosphorylated serine residues as non-canonical Ca²⁺-binding sites, sequestering amorphous calcium phosphate nanoclusters through electrostatic interactions to stabilize colloidal dispersions in extracellular fluids.^[33]^[34]^[35]^[36] Although less numerous than EF-hand proteins, which dominate the calcium-binding proteome across eukaryotes, non-EF-hand proteins are vital in specialized compartments, such as the ER for luminal buffering or the extracellular matrix for mineralization control.^[37]^[27]

Functions

Calcium Buffering

Calcium-binding proteins play a crucial role in maintaining low cytosolic Ca²⁺ concentrations by sequestering excess ions, thereby preventing cellular overload and stabilizing intracellular Ca²⁺ homeostasis. These proteins act as passive buffers that rapidly bind incoming Ca²⁺ during transient elevations, such as those triggered by influx through channels, reducing the amplitude and duration of free Ca²⁺ spikes. In cells with high buffer expression, such as fast-twitch skeletal muscle fibers, the total buffering capacity can reach millimolar levels; for instance, parvalbumin concentrations up to 1 mM enable the binding of substantial Ca²⁺ loads without saturating the system.^[38]^[39] The kinetics of Ca²⁺ binding to these proteins are optimized for effective buffering, featuring fast association rates that allow quick capture of free ions. Effective on-rates for parvalbumin are around 10⁵ M⁻¹ s⁻¹ under physiological conditions with Mg²⁺, enabling response to Ca²⁺ influxes on the millisecond timescale. In contrast, dissociation rates (off-rates) are slower, often around 1 s⁻¹ for parvalbumin, which supports sustained sequestration and gradual release, preventing abrupt Ca²⁺ rebounds while allowing eventual clearance by pumps and exchangers.^[38] The quantitative impact of buffering is profound in excitable cells like neurons, where it can attenuate free Ca²⁺ spikes by 50-90%, depending on buffer concentration and local Ca²⁺ dynamics. This reduction is quantified by the buffer power, defined as

\beta = \frac{d[\mathrm{Ca}^{2+}]_\mathrm{total}}{d[\mathrm{Ca}^{2+}]_\mathrm{free}},

which measures the change in total Ca²⁺ relative to free Ca²⁺ and highlights how buffers amplify the capacity to handle influx without proportional rises in free levels; for example, parvalbumin can yield β values exceeding 500 in fast-twitch muscle at resting Ca²⁺ levels (~50 nM), with lower but significant values (~50–200) in neuronal compartments.^[38]

Signal Transduction

Calcium-binding proteins serve as primary sensors in Ca²⁺-mediated signal transduction, detecting intracellular Ca²⁺ elevations and translating them into cellular responses by activating downstream effectors. Upon binding Ca²⁺ ions, these proteins undergo conformational changes that expose previously hidden interaction sites, enabling them to recruit and activate target molecules such as enzymes and ion channels. For instance, calmodulin (CaM), a ubiquitous EF-hand protein, binds up to four Ca²⁺ ions sequentially, with each binding event progressively exposing hydrophobic surfaces that facilitate interactions with effectors like myosin light-chain kinase in smooth muscle or nitric oxide synthase in endothelial cells.^[3] These proteins integrate into key signaling pathways by modulating the activity of kinases and phosphatases, thereby amplifying and propagating Ca²⁺ signals. CaM directly activates Ca²⁺/calmodulin-dependent protein kinases (CaMKs), such as CaMKII, which phosphorylate numerous substrates to elicit responses ranging from synaptic plasticity to gene expression; autophosphorylation of CaMKII at Thr286 generates partial Ca²⁺-independent activity, prolonging kinase function and amplifying signals by sustaining effector activation beyond transient Ca²⁺ spikes. Similarly, CaM recruits phosphatases like calcineurin (PP2B), whose regulatory domain becomes accessible upon Ca²⁺/CaM binding, dephosphorylating targets such as NFAT transcription factors to initiate immune responses. This kinase-phosphatase interplay can enhance signal strength through cascading phosphorylation events, with CaMKII exhibiting up to 70% autonomous activity post-autophosphorylation, effectively extending the duration and impact of Ca²⁺ transients.^[40]^[3] The specificity of Ca²⁺ signaling is decoded by variations in binding affinities among calcium-binding proteins, allowing discrimination between temporal patterns (fast versus slow transients) and spatial localization (e.g., microdomains near channels). Proteins with high Ca²⁺ affinity, such as neuronal calcium sensors (NCS) like hippocalcin (Kd ≈ 1–5 μM), respond to low-amplitude, prolonged Ca²⁺ rises in somatic or dendritic compartments, regulating transcription via CREB pathways, whereas lower-affinity binders like recoverin (Kd ≈ 2–10 μM) detect rapid, localized spikes in presynaptic microdomains to modulate phototransduction.^[41]^[42] This affinity gradient, combined with myristoylation for membrane targeting, ensures that fast synaptic Ca²⁺ influxes activate synapse-specific effectors while slower global waves engage broader cellular processes, preventing crosstalk and enabling precise signaling orchestration.

Physiological Roles

Cellular Signaling Pathways

Calcium-binding proteins play a crucial role in second messenger systems by modulating the propagation of Ca²⁺ waves, which are initiated through the activation of inositol 1,4,5-trisphosphate (IP₃) receptors on the endoplasmic reticulum. These waves facilitate intracellular communication by releasing stored Ca²⁺ into the cytosol, creating spatiotemporal patterns that trigger downstream effectors. Buffers such as calbindin influence wave dynamics through their diffusion properties, which restrict the spread of free Ca²⁺ and shape signal localization near release sites.^[43]^[44] These proteins also enable integration with other signaling pathways, particularly crosstalk between Ca²⁺ and cyclic AMP (cAMP)/protein kinase A (PKA) systems, allowing Ca²⁺ sensors to refine gene expression outcomes. In this interplay, elevated Ca²⁺ levels can activate adenylyl cyclases or inhibit phosphodiesterases, thereby altering cAMP concentrations and PKA activity to modulate transcription factors like CREB. This convergence ensures coordinated cellular responses, where Ca²⁺-bound proteins fine-tune PKA-mediated phosphorylation events for precise control over gene transcription.^[45]^[46] Feedback mechanisms involving calcium-binding proteins contribute to negative regulation of Ca²⁺ levels via pumps like the plasma membrane Ca²⁺-ATPase (PMCA) and sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA). Occupancy of these proteins by Ca²⁺ enhances pump activity, promoting rapid extrusion or reuptake to terminate signals and prevent overload. For instance, calmodulin binding to PMCA accelerates its function, forming a self-limiting loop that restores baseline Ca²⁺ concentrations. Similar dynamics apply to SERCA, where Ca²⁺-dependent interactions support efficient store refilling and signal quenching.^[47]^[48]

Tissue-Specific Functions

In muscle tissue, troponin C serves as a key calcium-binding protein that facilitates contraction by binding Ca²⁺ ions, which triggers a conformational change in the troponin complex to expose actin-myosin binding sites and enable cross-bridge cycling.^[49] This process is essential for the coordinated force generation in skeletal and cardiac muscles, where troponin C's regulatory sites respond rapidly to Ca²⁺ fluctuations during excitation-contraction coupling.^[50] In neuronal tissue, parvalbumin acts as a slow Ca²⁺ buffer that supports high-frequency firing by sequestering Ca²⁺ to limit peak free Ca²⁺ levels and reduce activation of Ca²⁺-dependent potassium channels, thereby preventing afterhyperpolarization and maintaining optimal intracellular Ca²⁺ levels for sustained action potential generation without overload.^[51] Similarly, calbindin contributes to synaptic plasticity in dendrites by buffering Ca²⁺ transients, which modulates signaling cascades involved in long-term potentiation and neuronal adaptability.^[52] In bone tissue, osteocalcin binds Ca²⁺ and hydroxyapatite to regulate mineralization, promoting the ordered deposition of calcium phosphate crystals during osteoblast activity and matrix maturation.^[53] In secretory tissues such as the mammary gland, caseins form micelles that sequester Ca²⁺ phosphate, ensuring stable delivery of bioavailable calcium in milk for neonatal development and preventing precipitation in secretory cells.^[54] Calcium-binding proteins exhibit adaptive expression in response to chronic Ca²⁺ stress; for instance, in the kidney under hypercalcemia, proteins like calbindin-D28k are regulated to enhance cytosolic buffering and protect against Ca²⁺ toxicity, maintaining homeostasis through transcellular transport adjustments.^[55]

Examples

Calmodulin Family

The calmodulin family comprises small, ubiquitous calcium-sensing proteins that play a central role in transducing calcium signals within eukaryotic cells. Calmodulin itself is a 148-amino-acid protein consisting of two globular domains, each containing a pair of EF-hand motifs capable of binding calcium ions, connected by a flexible central helical linker region.^[56] In the calcium-free state, calmodulin adopts a compact, globular conformation; however, upon binding four calcium ions—one to each EF-hand—it undergoes a conformational change to an extended dumbbell shape, exposing hydrophobic surfaces that facilitate interactions with target proteins.^[57] This structural versatility allows calmodulin to function as a prototypical calcium sensor within the EF-hand protein class.^[58] Activation of calmodulin requires the binding of at least four calcium ions, with the C-terminal domain exhibiting higher affinity than the N-terminal domain, enabling sequential binding and progressive conformational opening.^[59] Calcium-saturated calmodulin can then bind to and regulate over 300 diverse target proteins, modulating their activity in a calcium-dependent manner.^[59] A representative example is its interaction with myosin light-chain kinase in smooth muscle cells, where calcium-calmodulin binding relieves autoinhibition of the kinase, promoting phosphorylation of myosin regulatory light chains and thereby initiating contraction.^[60] This activation mechanism underscores calmodulin's role as a versatile mediator in calcium-regulated processes, with binding affinities tuned to physiological calcium transients. In humans, calmodulin is encoded by three genes—CALM1, CALM2, and CALM3—located on chromosomes 14q32.1, 2p21, and 19q13.3, respectively, producing the identical protein but with tissue-specific expression patterns.^[61]^[62]^[63] For instance, CALM2 shows elevated expression in neural tissues, contributing to calcium signaling in processes such as synaptic plasticity and learning.^[64] These genes maintain functional equivalence in most contexts but may confer subtle regulatory differences through variations in mRNA stability or local abundance, ensuring precise control of calcium-dependent pathways across tissues.^[65]

Calbindin and Parvalbumin

Calbindin-D9k, the predominant form in the mammalian intestine, is a small cytosolic protein with two EF-hand motifs that enable it to bind two calcium ions with high affinity, facilitating the transcellular transport of Ca²⁺ across enterocytes. This protein shuttles Ca²⁺ from the apical membrane, where it enters via channels like TRPV6, through the cytoplasm to the basolateral membrane for extrusion by PMCA1b or NCX1, thereby maintaining low cytosolic free Ca²⁺ levels to support efficient absorption.^[66] In the kidney, calbindin-D28k predominates, featuring six EF-hand domains organized into three pairs, of which four bind Ca²⁺ with medium to high affinity, aiding reabsorption in the distal convoluted tubule and connecting tubule. Similar to its intestinal counterpart, calbindin-D28k buffers intracellular Ca²⁺ during transcellular transport from apical TRPV5 entry to basolateral extrusion, preventing cytotoxicity and enhancing vectorial Ca²⁺ flux under regulation by vitamin D and parathyroid hormone.^[66] Parvalbumin, a 12 kDa protein expressed primarily in fast-spiking GABAergic interneurons of the central nervous system, contains three EF-hand domains, with two functional sites that bind Ca²⁺ and Mg²⁺ in a mixed mode, contributing to its role in synaptic Ca²⁺ buffering.^[67] These sites exhibit relatively rapid Ca²⁺ dissociation kinetics, with off-rates around 1–3 s⁻¹ at physiological temperatures, allowing parvalbumin to quickly release bound Ca²⁺ and modulate transient spikes during high-frequency neuronal firing.^[68] In fast-spiking interneurons, such as basket and chandelier cells, parvalbumin buffers Ca²⁺ influx at presynaptic terminals, shaping short-term synaptic plasticity by reducing facilitation and supporting sustained gamma oscillations critical for cognitive functions. Compared to calbindin isoforms, which prioritize steady-state Ca²⁺ transport and buffering in absorptive epithelia to handle prolonged fluxes, parvalbumin's faster on- and off-kinetics (on-rate up to 10⁸ M⁻¹ s⁻¹ in the absence of Mg²⁺) make it suited for dynamic, transient Ca²⁺ management in neurons, where it acts as a mobile buffer to accelerate decay of action potential-evoked transients without overly dampening signaling.^[67] This distinction underscores their specialized contributions to calcium homeostasis: calbindin in epithelial vectorial movement and parvalbumin in neuroprotective synaptic regulation.^[66]

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This review will outline several protocols we have used to identify which members and/or isoforms of this CaMK family mediate specific cellular responses.
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The cytoplasmic [Ca2+] ([Ca2+]c) under resting conditions is ∼10-7M, 104 times lower than [Ca2+] in the extracellular millieu (∼10-3M). Inside the cell, Ca2+ ...Missing: nM | Show results with:nM
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Parvalbumin is a slow Ca 2+ buffer that may affect the amplitude and time course of intracellular Ca 2+ transients in terminals after an action potential.
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Kinetic mechanism of calcium binding to whiting parvalbumin
The kinetics of calcium dissociation show a pronounced lag and are best fit by two rate constants of 1.2 and 3.0 s-1.Missing: off- source