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Local hormone

Local hormones are chemical signaling molecules produced by cells that act locally on neighboring cells (paracrine action) or the producing cell itself (autocrine action), without entering the systemic bloodstream to reach distant targets.^[1] Unlike endocrine hormones, which are secreted into the circulation for widespread physiological regulation, local hormones mediate short-range intercellular communication within specific tissues, often with rapid onset and short duration of action. This localized mode of action allows for precise control of cellular processes such as inflammation, tissue repair, and organ-specific homeostasis.^[2] The concept of local hormones encompasses a diverse group of substances, including eicosanoids like prostaglandins and leukotrienes, which are derived from arachidonic acid and play key roles in modulating vascular tone, pain sensation, and immune responses.^[2] For instance, prostaglandins such as PGE2 are synthesized on demand by most cells and exert effects like vasodilation or smooth muscle contraction in nearby tissues, without systemic distribution.^[3] Other prominent examples include somatostatin, produced by delta cells in the pancreas, which locally inhibits insulin and glucagon secretion to fine-tune glucose regulation.^[1] Additionally, molecules like nitric oxide and endothelins function as local hormones in the cardiovascular system, where they regulate blood vessel dilation and constriction in an autocrine or paracrine manner.^[4] Local hormones are integral to physiological adaptation and pathology, influencing processes from wound healing to allergic reactions.^[5] Their production is often triggered by local stimuli, such as injury or inflammation, and their effects are terminated quickly by enzymatic degradation, preventing spillover into broader circulation.^[2] In reproductive physiology, for example, prostaglandins act locally in the uterus to promote contractions during labor.^[2] Dysregulation of local hormone signaling contributes to conditions like chronic inflammation or hypertension, highlighting their therapeutic relevance in targeted drug development.^[6]

Overview

Definition

Local hormones are signaling molecules produced by various cells that exert their effects on nearby cells or the same producing cell without entering the bloodstream.^[7] These molecules, also known as autacoids, function over short distances and are typically derived from metabolic processes in various tissues, enabling precise, localized regulation of physiological responses.^[8] Key characteristics of local hormones include their rapid activation and inactivation, which ensures quick onset and termination of effects to maintain fine-tuned control. They are often released in response to physical activity or stress, facilitating immediate adjustments in tissue function. Local hormones often regulate the contraction and relaxation of smooth and vascular muscle, influencing processes such as blood flow and motility. The intensity of the response depends on the concentration of specific receptors on target cells and the quantity of the ligand available, allowing for graded signaling based on local needs.^[7]^[9]^[10] Local hormones are synthesized by various cells, including those in endocrine tissues, neurons, and other tissues, where they are produced on demand rather than stored in large quantities. This decentralized production supports their role in autocrine and paracrine signaling, acting within the immediate cellular environment.^[11] The concept of local hormones gained recognition in the mid-20th century as distinct from systemic circulating hormones, building on earlier observations of tissue-specific mediators. Initial studies in the 1940s and 1950s, particularly on gastrointestinal secretions, highlighted their localized actions in regulating digestive processes, as discussed in physiological forums like the 1950 Royal Society discussion led by J. H. Burn, featuring contributions from Wilhelm Feldberg.^[12]^[13]

Distinction from systemic hormones

Systemic hormones, also known as endocrine hormones, are secreted by specialized glands such as the pituitary or thyroid and enter the bloodstream to reach distant target cells throughout the body, enabling widespread physiological regulation.^[1] In contrast, local hormones operate through short-range diffusion within tissues, acting on nearby cells without entering the vascular circulation, which confines their influence to specific microenvironments.^[14] A key difference lies in their pharmacokinetics: systemic hormones often exhibit longer half-lives, ranging from minutes to hours, allowing sustained effects on remote organs, as seen with insulin's role in global blood glucose homeostasis.^[1] Local hormones, however, are rapidly degraded, with half-lives typically in seconds to minutes, preventing unintended spread and ensuring transient, site-specific actions; for instance, prostaglandins are inactivated almost immediately after local release to avoid broader interference.^[15] This localized scope of local hormones facilitates precise, compartmentalized control in processes like inflammation or digestion, minimizing systemic side effects that can arise from endocrine hormones' broader distribution.^[7] By contrast, endocrine hormones coordinate organism-wide responses but risk off-target impacts due to their circulatory travel.^[14] From an evolutionary standpoint, local signaling mechanisms, such as paracrine pathways, represent an ancient form of cellular communication that predates the development of vascular systems, with endocrine signaling emerging later as multicellular organisms evolved circulatory networks to extend signal range.^[16]

Mechanisms of Action

Paracrine mechanism

Paracrine signaling represents a key mechanism by which local hormones exert their effects on neighboring cells within the same tissue, distinguishing it from longer-range endocrine signaling. In this process, a producing cell secretes the hormone into the extracellular space, where it diffuses over short distances—typically micrometers to millimeters—to reach target cells in close proximity.^[17] This localized action ensures precise coordination of cellular activities without widespread systemic influence, as the signal is rapidly degraded, taken up, or bound to the extracellular matrix to prevent farther diffusion.^[17] The diffusion of local hormones occurs primarily through the interstitial fluid, allowing the molecule to travel from the secreting cell to adjacent targets without entering the bloodstream. Upon arrival, the hormone binds to specific receptors on the target cell's surface or interior, often with high affinity (dissociation constants around 10^{-8} to 10^{-9} M). Common receptor types include G-protein-coupled receptors (GPCRs), which activate intracellular pathways via heterotrimeric G proteins, and receptor tyrosine kinases (RTKs), which undergo autophosphorylation to initiate signaling cascades. These activations typically lead to the production of second messengers, such as cyclic AMP (cAMP) in the case of GPCRs, which amplify the signal by modulating protein kinases and ion channels within the cell.^[18]^[17] Physiologically, paracrine mechanisms play crucial roles in tissue development, where they facilitate embryonic patterning and cell differentiation; for instance, fibroblast growth factors (FGFs) act as paracrine signals to guide mesenchymal-epithelial interactions during organ formation. In inflammation, local hormones mediate rapid responses by recruiting and activating nearby immune cells, promoting vasodilation and cytokine release to contain tissue damage. Additionally, these signals maintain local homeostasis, such as regulating pH and enzyme secretion in specialized tissues, ensuring balanced microenvironments without disrupting distant organs.^[19]^[17]

Autocrine mechanism

Autocrine signaling refers to a mechanism in which a cell produces and secretes a local hormone that binds to receptors on its own surface, thereby influencing its own physiological state without affecting neighboring cells. This self-targeted action allows for rapid, localized regulation of cellular functions, distinguishing it from broader intercellular communication. In the context of local hormones, autocrine loops enable precise control over processes such as growth and differentiation by confining the signal to the producing cell.^[20] The process begins immediately after secretion, with the hormone engaging its receptor on the same cell, often triggering intracellular signaling cascades. For instance, growth factors acting via autocrine pathways frequently activate the JAK-STAT pathway, where ligand binding leads to phosphorylation of receptor-associated Janus kinases (JAKs), which in turn phosphorylate signal transducer and activator of transcription (STAT) proteins. These activated STATs translocate to the nucleus to modulate gene expression, promoting outcomes like cell proliferation or, in certain contexts, apoptosis to maintain homeostasis. This direct receptor engagement ensures efficient signal transduction without reliance on diffusion, amplifying or inhibiting the cell's response through positive or negative feedback loops inherent to the system.^[21]^[22] Physiologically, autocrine mechanisms play critical roles in immune cell activation, where, for example, T cells utilize autocrine purinergic signaling via ATP release to induce calcium influx and enhance their activation and proliferation during immune responses. In tumor progression, autocrine loops are prevalent, as cancer cells secrete growth factors that bind to self-receptors, fostering uncontrolled proliferation and survival, thereby promoting tumor growth. Additionally, autocrine signaling contributes to tissue repair, as seen in wound healing where hypoxia-induced IL-24 acts autocrinely on keratinocytes and fibroblasts via STAT3 to coordinate re-epithelialization and extracellular matrix remodeling. These roles underscore autocrine signaling's importance in self-regulation across diverse tissues.^[23]^[24]^[25] A key feature of autocrine mechanisms is their capacity to establish negative feedback loops that prevent overproduction of the hormone, such as when ligand-receptor binding inhibits further ligand synthesis, thereby maintaining cellular balance. This contrasts with paracrine signaling, which targets adjacent cells for coordinated tissue-level responses, highlighting autocrine's focus on intrinsic cellular feedback for amplification or restraint. Such loops ensure adaptive responses without systemic involvement, aligning with the localized nature of these hormones.^[26]

Juxtacrine and intracrine mechanisms

Juxtacrine signaling represents a form of local hormone action that requires direct physical contact between cells, mediated by membrane-bound ligands interacting with receptors on adjacent cells without the involvement of diffusible molecules. Unlike paracrine mechanisms that depend on short-range diffusion, juxtacrine ensures precise, contact-dependent communication, often involving cell adhesion molecules to maintain proximity. This process typically activates signaling cascades through receptor-ligand binding at the plasma membrane, leading to intracellular events such as proteolytic cleavage or phosphorylation.^[27]^[28] A prominent example of juxtacrine signaling is the Notch pathway, where membrane-anchored ligands like Delta or Jagged on a signaling cell bind to the Notch receptor on a neighboring cell, inducing sequential cleavages by ADAM and gamma-secretase proteases to release the Notch intracellular domain (NICD). The NICD then translocates to the nucleus, forming a complex with transcription factors such as CSL and Mastermind to directly regulate target gene expression. Membrane-bound forms of growth factors, such as heparin-binding EGF-like growth factor (HB-EGF), also exemplify this mechanism by activating epidermal growth factor receptors (EGFR) on adjacent cells to influence processes like tight junction regulation in epithelial tissues.^[27]^[29] Physiologically, juxtacrine signaling plays a critical role in developmental processes, particularly cell differentiation and patterning during embryogenesis; for instance, Notch-mediated lateral inhibition helps specify distinct cell fates in the nervous system of vertebrates and invertebrates. In endocrine tissues, it coordinates hormone production, as seen in pituitary cells where gap junctions facilitate synchronized prolactin transcription among contacting lactotrophs, enabling rapid, tissue-scale responses to stimuli like suckling. These roles highlight juxtacrine's importance in contexts requiring high spatial precision, such as organogenesis and localized tissue homeostasis.^[27]^[28] Intracrine signaling, in contrast, involves local hormones acting entirely within the producing cell or after uptake into target cells, binding to cytoplasmic or nuclear receptors without export to the extracellular milieu. This mechanism bypasses surface receptors and the extracellular space, allowing hormones to directly modulate intracellular targets like transcription factors or enzymes, often through nuclear translocation or feed-forward regulatory loops. The concept of intracrine action was introduced in 1984 to describe peptide hormones functioning internally, expanding beyond traditional endocrine or paracrine paradigms.^[30]^[31] Key examples include basic fibroblast growth factor (FGF2), which enters the nucleus to interact with ribosomal proteins and influence cell proliferation, and parathyroid hormone-related protein (PTHrP), whose nuclear localization domain enables binding to cyclin D1 promoters to drive cell cycle progression. Angiotensin II demonstrates intracrine regulation by acting within vascular smooth muscle cells to upregulate its own biosynthetic enzymes, such as renin and angiotensinogen, forming aut amplificatory loops. These processes often involve vesicular trafficking, exosomes, or direct nuclear import to facilitate hormone-receptor interactions.^[30]^[32] Intracrine mechanisms are essential for fine-tuned gene expression control and cell differentiation, particularly in development, where they support stem cell fate decisions and tissue-specific responses, such as in cardiac embryogenesis via PTHrP. Though rarer than extracellular signaling, their roles are pivotal in precise physiological contexts like localized proliferation during wound healing or organ development, and dysregulation contributes to pathologies including cancer and cardiovascular disease.^[30]^[31]

Gastrointestinal Local Hormones

Gastrin family

The gastrin family consists of peptide hormones primarily involved in gastrointestinal regulation, including gastrin and cholecystokinin (CCK), both derived from larger preprohormones through post-translational processing. Gastrin is synthesized as preprogastrin in G cells of the gastric antrum and processed into amidated forms such as G-17 (17 amino acids) and G-34 (34 amino acids), with bioactivity concentrated in the conserved C-terminal pentapeptide sequence shared with CCK.^[33] CCK, produced by I cells in the duodenum and jejunum from preprocholecystokinin, yields multiple forms including CCK-33 (33 amino acids), CCK-22, CCK-8, and the full-length CCK-58, also featuring the identical bioactive C-terminal pentapeptide (Gly-Trp-Met-Asp-Phe-NH₂).^[34] These structural similarities enable overlapping receptor interactions, though their primary sites of action differ within the digestive system.^[35] Gastrin primarily stimulates gastric acid secretion by binding to cholecystokinin-2 receptors (CCK2R) on enterochromaffin-like (ECL) cells, prompting histamine release that activates parietal cells via H2 receptors, while also promoting gastric mucosal growth and inhibiting epithelial cell apoptosis.^[33] In contrast, CCK acts paracrine in the GI tract to induce gallbladder contraction for bile release and pancreatic enzyme secretion for fat and protein digestion, mediated mainly by CCK1 receptors (CCK1R) on smooth muscle and acinar cells; it also slows gastric emptying to optimize nutrient absorption.^[34] Both hormones operate through G-protein-coupled receptors: CCK1R shows high selectivity for sulfated CCK peptides and couples to Gq/PLC/Ca²⁺ pathways, whereas CCK2R binds both gastrin and CCK with similar affinity, activating additional signaling like MAPK and PI3K/AKT for trophic effects.^[35] Regulation of the gastrin family occurs mainly in response to luminal nutrients, with gastrin release triggered by peptides, amino acids, and gastric distension via vagal stimulation and gastrin-releasing peptide (GRP), while low pH and somatostatin from D cells provide feedback inhibition to prevent excessive acid production.^[33] CCK secretion is elicited by dietary fats and proteins binding to GPR40 on I cells, leading to intracellular calcium mobilization and vagal afferent signaling, with somatostatin similarly modulating its release to coordinate digestion.^[34] These hormones exemplify paracrine mechanisms, diffusing locally to nearby target cells without entering systemic circulation.^[35] Clinically, elevated gastrin levels (hypergastrinemia) contribute to peptic ulcers through unchecked acid hypersecretion, notably in Zollinger-Ellison syndrome caused by gastrinomas—neuroendocrine tumors autonomously secreting gastrin, often exceeding 1000 pg/mL and diagnosable via secretin stimulation tests.^[36] Recent studies highlight CCK's role in appetite suppression, where CCK-58 binding to vagal CCK1R reduces meal size and extends satiety intervals, though full agonists have shown limited efficacy in obesity trials due to nausea, prompting exploration of combination therapies.^[37] Overexpression of gastrin or CCK signaling is implicated in gastrointestinal malignancies, including gastric and pancreatic cancers, underscoring their trophic potential.^[35]

Secretin family

The secretin family comprises structurally related peptides that play key roles in gastrointestinal (GI) and pancreatic regulation, including secretin, glucagon, glicentin, vasoactive intestinal peptide (VIP), gastric inhibitory polypeptide (GIP), and glucagon-like peptide-1 (GLP-1). Although many exhibit both local and systemic effects, this section emphasizes their paracrine and autocrine roles within the GI tract and pancreas. These hormones share significant sequence homology, particularly in their amphipathic α-helical N-terminal regions essential for receptor binding, and are encoded by distinct genes but exhibit overlapping expression in enteroendocrine cells of the gut and pancreas. Secretin and GIP are primarily produced in the duodenum, glucagon and glicentin derive from proglucagon processing in pancreatic α-cells and intestinal L-cells, while VIP is synthesized in enteric neurons.^[38] Secretin, a 27-amino-acid peptide released from duodenal S-cells in response to luminal acidity, inhibits gastric acid secretion from parietal cells and stimulates bicarbonate-rich fluid secretion from pancreatic ductal cells to maintain duodenal pH homeostasis. Glucagon, a 29-amino-acid peptide, acts both endocrinely on the liver to promote glycogenolysis and gluconeogenesis and paracrinely within pancreatic islets to modulate insulin and somatostatin secretion, aiding local glucose regulation.^[39] VIP, a 28-amino-acid neuropeptide, relaxes GI smooth muscle and stimulates water and electrolyte secretion, facilitating coordinated motility and vasodilation. GIP, a 42-amino-acid incretin from duodenal K-cells, potentiates glucose-dependent insulin release from pancreatic β-cells. Glicentin, a 69-amino-acid proglucagon-derived peptide containing the full glucagon sequence, inhibits gastric acid secretion.^[40] All family members signal through class B G-protein-coupled receptors (GPCRs), which couple to Gs proteins to elevate intracellular cyclic AMP (cAMP) levels, thereby activating protein kinase A and downstream effectors. These peptides are regulated primarily through paracrine and autocrine mechanisms in the intestines and pancreas, with secretion triggered by luminal stimuli such as low pH for secretin or nutrient ingestion (fats, carbohydrates, proteins) for GIP and glicentin. Neural inputs and hormonal feedback, including inhibition by somatostatin, further modulate their release, ensuring coordinated postprandial responses. Degradation occurs rapidly via dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase, limiting their systemic half-life and emphasizing local actions. Clinically, glucagon is administered to counteract severe hypoglycemia in diabetes management by rapidly mobilizing hepatic glucose stores.^[39] VIP exhibits anti-inflammatory properties, with analogs showing promise in treating inflammatory bowel disease (IBD) by enhancing epithelial barrier integrity and suppressing Th1-driven inflammation in preclinical models.^[41] In the 2020s, GIP's role has gained prominence through dual GIP/GLP-1 receptor agonists like tirzepatide, approved in 2022, which enhance insulin secretion, promote satiety, and achieve superior weight loss in obesity and type 2 diabetes compared to GLP-1 monotherapy.^[42]

Eicosanoid Local Hormones

Prostaglandins

Prostaglandins are a class of lipid-derived local hormones known as eicosanoids, consisting of 20-carbon unsaturated fatty acids with a cyclopentane ring structure. They are primarily synthesized from the polyunsaturated fatty acid arachidonic acid, which is released from cell membrane phospholipids. As local mediators, prostaglandins exert their effects primarily through paracrine signaling on nearby cells due to their short biological half-life of 1 to 2 minutes.^[2]^[15]^[43] The biosynthesis of prostaglandins begins with the activation of phospholipase A2, which liberates arachidonic acid from membrane glycerophospholipids in response to cellular stimuli such as injury or inflammation. This free arachidonic acid is then converted by the rate-limiting enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) into the unstable endoperoxide intermediate prostaglandin H2 (PGH2); COX-1 is constitutively expressed for basal functions, while COX-2 is inducible under inflammatory conditions. PGH2 serves as a common precursor that is further metabolized by specific terminal synthases or isomerases—such as prostaglandin E synthase for PGE2 or prostaglandin F synthase for PGF2α—into distinct prostaglandin subtypes, which are then rapidly released to act locally.^[2]^[44]^[45] Prostaglandins play diverse roles in physiological and pathological processes, particularly in inflammation and reproduction. In inflammation, PGE2 promotes vasodilation, enhances vascular permeability to facilitate immune cell infiltration, sensitizes nociceptors to amplify pain signaling, and acts on the hypothalamus to induce fever by raising the thermoregulatory set point. PGI2 contributes to regulating blood flow through vasodilation in vascular endothelium and inhibits platelet aggregation to prevent excessive clotting, thereby maintaining vascular homeostasis. In reproduction, PGF2α and PGE2 are critical for inducing uterine contractions and cervical ripening during labor; for instance, synthetic analogs like dinoprostone (PGE2) and carboprost (PGF2α) are used clinically to initiate labor.^[2]^[15]^[46] Clinically, prostaglandins are targeted for their roles in pain and inflammation, with non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin inhibiting COX enzymes to suppress prostaglandin synthesis and thereby reduce these symptoms. COX-2 selective inhibitors, like celecoxib, offer advantages by sparing COX-1-mediated protective effects in the gastrointestinal tract while targeting inducible prostaglandin production. Recent research in the 2020s has explored COX-2 inhibitors for cancer prevention, showing associations with improved survival in certain cancers due to reduced prostaglandin-driven tumor promotion and angiogenesis, as evidenced in real-world data analyses of NSAID use in oncology patients.^[2]^[47]^[48]

Leukotrienes

Leukotrienes are a class of eicosanoid local hormones derived from arachidonic acid, distinct from prostaglandins in their biosynthesis pathway and primary roles in immune responses.^[49] These lipid mediators are linear, 20-carbon chain molecules produced predominantly by leukocytes through the 5-lipoxygenase (5-LO) pathway.^[50] The pathway begins with the release of arachidonic acid from membrane phospholipids by phospholipase A2, followed by its oxygenation at the 5-position by 5-LO to form 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is then converted to leukotriene A4 (LTA4), the common precursor for all leukotrienes.^[51] Biosynthesis of leukotrienes requires the 5-lipoxygenase-activating protein (FLAP), an integral membrane protein that facilitates the translocation of 5-LO to the nuclear envelope and transfers arachidonic acid to the enzyme, enabling efficient production at sites of inflammation.^[52] This process occurs rapidly in activated leukocytes, such as mast cells, eosinophils, and macrophages, leading to the generation of dihydroxy leukotriene B4 (LTB4) from LTA4 via LTA4 hydrolase, or cysteinyl leukotrienes (LTC4, LTD4, LTE4) through sequential addition of glutathione and its derivatives by leukotriene C4 synthase and downstream enzymes.^[50] Once synthesized, leukotrienes act locally in a paracrine manner, diffusing to nearby cells to bind G-protein-coupled receptors: BLT1 and BLT2 for LTB4, and CysLT1 and CysLT2 for cysteinyl leukotrienes, thereby amplifying inflammatory signals without systemic circulation.^[53] LTB4 primarily functions as a potent chemoattractant, recruiting neutrophils to sites of inflammation and promoting their adhesion, degranulation, and superoxide production to enhance antimicrobial defenses.^[54] In contrast, cysteinyl leukotrienes (LTC4, LTD4, LTE4) mediate allergic and asthmatic responses by inducing bronchoconstriction through smooth muscle contraction in the airways, increasing vascular permeability to cause edema, and stimulating mucus hypersecretion, effects that are 100 to 1,000 times more potent than those of histamine.^[55] These actions contribute to the pathophysiology of asthma and allergic rhinitis, where elevated leukotriene levels correlate with disease severity.^[56] Clinically, leukotrienes are targeted in asthma management with montelukast, a selective CysLT1 receptor antagonist that blocks the effects of cysteinyl leukotrienes, reducing bronchoconstriction, airway inflammation, and exacerbations, particularly in patients with exercise-induced or allergic asthma.^[57] In the 2020s, studies have linked dysregulated leukotriene production to cytokine storms in severe COVID-19, where elevated LTB4 and cysteinyl leukotrienes exacerbate pulmonary inflammation and multi-organ damage, prompting investigations into leukotriene modifiers as adjunct therapies to mitigate hyperinflammation.^[58]^[59]

Other Local Hormones

Histamine and serotonin

Histamine is an amino acid-derived local hormone synthesized from L-histidine through decarboxylation by the enzyme L-histidine decarboxylase, utilizing pyridoxal-5’-phosphate as a cofactor.^[60] It is primarily stored in granules within mast cells and basophils, where it associates with heparin in mast cells and chondroitin-4-sulfate in basophils.^[60] Upon stimulation, such as during allergic responses, these cells undergo degranulation, leading to rapid local release of histamine that acts in a paracrine manner to influence nearby tissues.^[61] In allergic reactions, histamine binds to H1 receptors, which are Gq-protein-coupled and predominantly expressed on endothelial cells, smooth muscle, and sensory nerves; this activation causes vasodilation, increased vascular permeability, and itching (pruritus).^[60] Additionally, H1 receptor signaling contributes to bronchoconstriction and other immediate hypersensitivity symptoms.^[60] For gastric acid secretion, histamine acts paracrine on H2 receptors—Gs-protein-coupled—located on parietal cells in the stomach mucosa, stimulating cyclic AMP production and subsequent acid release.^[60] Histamine also interacts with H3 and H4 receptors, which are Gi/o-coupled and involved in modulating neurotransmitter release and immune cell chemotaxis, respectively, further extending its local regulatory roles.^[60] Serotonin, also known as 5-hydroxytryptamine (5-HT), is another biogenic amine local hormone derived from the essential amino acid L-tryptophan, converted via tryptophan hydroxylase 1 (TPH1) in peripheral tissues.^[62] Approximately 90-95% of the body's serotonin is produced and stored in enterochromaffin cells of the gastrointestinal mucosa and in platelets, which uptake serotonin from plasma via the serotonin transporter (SERT).^[62] Upon triggers like mechanical stimulation or inflammation, serotonin is released locally from these stores, exerting paracrine effects through diffusion to adjacent cells.^[63] In the gut, serotonin promotes motility by activating 5-HT3 and 5-HT4 receptors on enteric neurons and smooth muscle, initiating peristalsis and segmentation contractions essential for propulsion and mixing of contents.^[62] It also induces vasoconstriction in submucosal arterioles via 5-HT2 receptors, regulating local blood flow and nutrient absorption.^[62] Furthermore, platelet-released serotonin facilitates aggregation and hemostasis at sites of vascular injury, underscoring its role in local thrombosis control.^[62] Serotonin's actions are mediated by seven families of G-protein-coupled receptors (5-HT1 to 5-HT7), along with the ionotropic 5-HT3 receptor, allowing diverse paracrine signaling in tissues like the gut and vasculature.^[62] Both histamine and serotonin function through rapid paracrine mechanisms, with release often triggered by degranulation or exocytosis, enabling quick responses in allergic, inflammatory, and neural contexts; their G-protein-coupled receptors amplify signals via second messengers like IP3, cAMP, or calcium influx.^[60]^[62] Clinically, H1 receptor antagonists (first- and second-generation antihistamines like diphenhydramine and loratadine) are first-line treatments for allergic conditions, blocking itching, vasodilation, and rhinitis symptoms, while H2 antagonists (e.g., ranitidine) reduce gastric acid secretion in conditions like peptic ulcers.^[64] Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, indirectly modulate local serotonin levels by inhibiting SERT, potentially altering gut motility and contributing to side effects like nausea or diarrhea in gastrointestinal disorders.^[63] Recent 2020s research highlights serotonin's role in the gut-brain axis, where enteric serotonin influences mood and cognition via microbiota interactions and vagal signaling, informing novel mental health therapies targeting peripheral 5-HT pathways.^[65]

Kinins and angiotensin

Kinins are a class of peptide local hormones generated through the enzymatic cleavage of kininogens by kallikreins, primarily producing bradykinin and kallidin (also known as lysyl-bradykinin).^[66] Kallidin is formed first and rapidly converted to bradykinin by plasma aminopeptidase, with tissue and plasma kallikreins playing key roles in this activation process.^[66] These kinins act locally in a paracrine manner within vascular and inflammatory tissues, exerting effects on pain transmission, vasodilation, and vascular permeability primarily through activation of B1 and B2 receptors.^[6] The biological functions of kinins are mediated via two G-protein-coupled receptor subtypes: B2 receptors, which are constitutively expressed and handle acute responses, and inducible B1 receptors, which contribute to chronic inflammation.^[66] Bradykinin, in particular, induces pain transmission by sensitizing nociceptors through B2 receptor activation, leading to hyperalgesia in inflammatory conditions.^[67] It promotes vasodilation in arteries and veins, such as those in the gut and aorta, by stimulating nitric oxide release and smooth muscle relaxation.^[66] Additionally, kinins increase vascular permeability via both receptor types, facilitating plasma extravasation and edema formation during local inflammatory responses.^[6] Angiotensin II (Ang II), another key peptide local hormone, is produced from angiotensinogen through the renin-angiotensin system (RAS), involving renin cleavage to angiotensin I followed by conversion via angiotensin-converting enzyme (ACE).^[68] Locally in tissues like the kidneys and adrenals, Ang II exerts paracrine effects, including vasoconstriction of arterioles to regulate blood flow and pressure.^[68] It also stimulates aldosterone release from the adrenal cortex zona glomerulosa, enhancing sodium reabsorption in the distal nephron and contributing to fluid balance.^[68] Both kinins and Ang II are activated via enzymatic cleavage and operate through G-protein-coupled receptors in a paracrine fashion within tissues such as the vasculature and kidneys.^[69] Kinins bind B1/B2 receptors, triggering phospholipase C activation, intracellular calcium mobilization, and downstream pathways like MAPK for vascular and inflammatory signaling.^[66] Similarly, Ang II engages AT1 receptors to initiate Gq-protein coupling, phospholipase C hydrolysis, and calcium signaling, leading to vasoconstriction and cellular proliferation.^[70] Clinically, the interplay between these systems is evident in hypertension management, where ACE inhibitors block Ang II formation while accumulating kinins, enhancing vasodilation but risking bradykinin-mediated angioedema due to reduced degradation.^[71] Bradykinin elevation from ACE inhibition contributes to this angioedema, characterized by non-pitting edema in subcutaneous tissues.^[72] Recent 2020s research highlights the local RAS's role in COVID-19 vascular damage, where SARS-CoV-2 downregulates ACE2, leading to unchecked Ang II accumulation, endothelial dysfunction, and increased thrombosis risk.^[73]

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Cholecystokinin (CCK) is a peptide hormone linked to the gastrointestinal (GI) system. The receptors are expressed in the central nervous system.
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Jul 6, 2023 · Loss of ACE2 on vascular endothelium can therefore exacerbate inflammation, thrombosis, and endothelial dysfunction., Damage to the endothelial ...