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Local hormone
Local hormone
Local hormone
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Local hormones are a large group of signaling molecules that do not circulate within the blood. Local hormones are produced by nerve and gland cells and bind to either neighboring cells or the same type of cell that produced them. Local hormones are activated and inactivated quickly.[1] They are released during physical work and exercise. They mainly control smooth and vascular muscle dilation.[2] Strength of response is dependent upon the concentration of receptors of target cell and the amount of ligand ( the specific local hormone).[3]

Eicosanoids (ī′kō-să-noydz; eicosa = twenty, eidos = formed) are a primary type of local hormone. These local hormones are polyunsaturated fatty acid derivatives containing 20 carbon atoms and fatty acids derived from phospholipids in the cell membrane or from diet. Eicosanoids initiate either autocrine stimulation or paracrine stimulation. There are two main types of eicosanoids: prostaglandins and leukotrienes, which initiate either autocrine stimulation or paracrine stimulation. Eicosanoids are the result of a ubiquitous pathway which first produces arachidonic acid, and then the eicosanoid product.

Prostaglandins are the most diverse category of eicosanoids and are thought to be synthesized in most tissues of the body. This type of local hormone stimulates pain receptors and increases the inflammatory response. Nonsteroidal anti-inflammatory drugs stop the formation of prostaglandins, thus inhibiting these responses.

Leukotrienes are a type of eicosanoids that are produced in leukocytes and function in inflammatory mediation.[4]

Paracrines (para- = beside or near) are local hormones that act on neighboring cells.[1] This type of signaling involves the secretion of paracrine factors, which travel a short distance in the extracellular environment to affect nearby cells. These factors can be excitatory or inhibitory. There are a few families of factors that are very important in embryo development including fibroblast growth factor secreted them.[1]

Juxtacrines (juxta = near) are local hormones that require close contact and act on either the cell which emitted them or on adjacent cells.[5]

Classification

[edit]

According to structural and functional similarity, many local hormones fall into either the gastrin or the secretin family.[6]

Gastrin family

[edit]

The Gastrin family is a group of peptides evolutionarily similar in structure and function. Commonly synthesized in antroduodenal G-cells. Regulate gastric function along with gastric acid secretion and mucosal growth.[7]

  1. Gastrin
  2. Cholecystokinin (CCK)

Secretin family

[edit]

The Secretin family are peptides that act as local hormones which regulate activity of G-protein coupled receptors. Most often found in the pancreas and the intestines. Secretin was discovered in 1902 by E. H. Starling. It was later linked to chemical regulation and was the first substance to be deemed a hormone.[8]

  1. Secretin
  2. Glucagon
  3. Glicentin (GLI)
  4. Vasoactive intestinal peptide (VIP)
  5. Gastric inhibitory polypeptide (GIP)

Others

[edit]
  1. Motilin
  2. Neurotensin
  3. Substance P
  4. Somatostatin
  5. Bombesin
  6. Serotonin
  7. Angiotensin
  8. Nitric Oxide
  9. Kinins
  10. Histamine

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Local hormone

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from Grokipedia
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. 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 , tissue repair, and organ-specific . The concept of local hormones encompasses a diverse group of substances, including eicosanoids like prostaglandins and leukotrienes, which are derived from and play key roles in modulating vascular tone, pain sensation, and immune responses. For instance, prostaglandins such as PGE2 are synthesized on demand by most cells and exert effects like or smooth muscle contraction in nearby tissues, without systemic distribution. Other prominent examples include , produced by delta cells in the , which locally inhibits insulin and glucagon secretion to fine-tune glucose . Additionally, molecules like and endothelins function as local hormones in the cardiovascular system, where they regulate dilation and in an autocrine or paracrine manner. Local hormones are integral to physiological adaptation and pathology, influencing processes from to allergic reactions. Their production is often triggered by local stimuli, such as or , and their effects are terminated quickly by enzymatic degradation, preventing spillover into broader circulation. In reproductive , for example, prostaglandins act locally in the to promote contractions during labor. Dysregulation of local hormone signaling contributes to conditions like chronic or , highlighting their therapeutic relevance in targeted .

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. 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. 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 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 . 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. 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 , acting within the immediate cellular environment. The 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 and , 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. , featuring contributions from Wilhelm Feldberg.

Distinction from systemic hormones

Systemic hormones, also known as endocrine hormones, are secreted by specialized glands such as the pituitary or and enter the bloodstream to reach distant target cells throughout the body, enabling widespread physiological regulation. 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. 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 . 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. This localized scope of local hormones facilitates precise, compartmentalized control in processes like or , minimizing systemic side effects that can arise from endocrine hormones' broader distribution. By contrast, endocrine hormones coordinate organism-wide responses but risk off-target impacts due to their circulatory travel. 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.

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. 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. 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. 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 , local hormones mediate rapid responses by recruiting and activating nearby immune cells, promoting and release to contain tissue damage. Additionally, these signals maintain local , such as regulating and in specialized tissues, ensuring balanced microenvironments without disrupting distant organs.

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. The process begins immediately after , with the 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 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 , promoting outcomes like or, in certain contexts, to maintain . This direct receptor engagement ensures efficient without reliance on , amplifying or inhibiting the cell's response through positive or negative feedback loops inherent to the system. Physiologically, autocrine mechanisms play critical roles in immune cell , where, for example, T cells utilize autocrine purinergic signaling via ATP release to induce calcium influx and enhance their 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 , thereby promoting tumor growth. Additionally, autocrine signaling contributes to tissue repair, as seen in wound healing where hypoxia-induced IL-24 acts autocrinely on and fibroblasts via to coordinate re-epithelialization and remodeling. These roles underscore autocrine signaling's importance in self-regulation across diverse tissues. A key feature of autocrine mechanisms is their capacity to establish loops that prevent overproduction of the , such as when -receptor binding inhibits further ligand synthesis, thereby maintaining cellular balance. This contrasts with , 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 of these hormones.

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 , juxtacrine ensures precise, contact-dependent communication, often involving molecules to maintain proximity. This process typically activates signaling cascades through receptor-ligand binding at the plasma , leading to intracellular events such as proteolytic cleavage or . 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. Physiologically, juxtacrine signaling plays a critical role in developmental processes, particularly cell differentiation and patterning during embryogenesis; for instance, Notch-mediated helps specify distinct cell fates in the of vertebrates and . 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 and localized tissue . 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. Key examples include basic fibroblast growth factor (FGF2), which enters the nucleus to interact with ribosomal proteins and influence , and (PTHrP), whose nuclear localization domain enables binding to promoters to drive progression. II demonstrates regulation by acting within vascular 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. Intracrine mechanisms are essential for fine-tuned control and cell differentiation, particularly in development, where they support 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 or organ development, and dysregulation contributes to pathologies including cancer and .

Gastrointestinal Local Hormones

Gastrin family

The family consists of peptide hormones primarily involved in gastrointestinal regulation, including and cholecystokinin (CCK), both derived from larger preprohormones through post-translational processing. is synthesized as preprogastrin in G cells of the gastric antrum and processed into amidated forms such as G-17 (17 ) and G-34 (34 ), with bioactivity concentrated in the conserved C-terminal pentapeptide sequence shared with CCK. CCK, produced by I cells in the and from preprocholecystokinin, yields multiple forms including CCK-33 (33 ), CCK-22, CCK-8, and the full-length CCK-58, also featuring the identical bioactive C-terminal pentapeptide (Gly-Trp-Met-Asp-Phe-NH₂). These structural similarities enable overlapping receptor interactions, though their primary sites of action differ within the digestive system. Gastrin primarily stimulates gastric acid secretion by binding to cholecystokinin-2 receptors (CCK2R) on enterochromaffin-like (ECL) cells, prompting release that activates parietal cells via H2 receptors, while also promoting gastric mucosal growth and inhibiting epithelial cell . In contrast, CCK acts paracrine in the GI tract to induce contraction for release and pancreatic secretion for and protein , mediated mainly by CCK1 receptors (CCK1R) on and acinar cells; it also slows gastric emptying to optimize absorption. 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 and CCK with similar affinity, activating additional signaling like MAPK and PI3K/AKT for trophic effects. Regulation of the gastrin family occurs mainly in response to luminal nutrients, with release triggered by peptides, , and gastric distension via vagal stimulation and (GRP), while low and from D cells provide feedback inhibition to prevent excessive production. 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 similarly modulating its release to coordinate . These hormones exemplify paracrine mechanisms, diffusing locally to nearby target cells without entering systemic circulation. Clinically, elevated levels (hypergastrinemia) contribute to peptic ulcers through unchecked acid hypersecretion, notably in Zollinger-Ellison syndrome caused by gastrinomas—neuroendocrine tumors autonomously secreting , often exceeding 1000 pg/mL and diagnosable via stimulation tests. 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 trials due to , prompting exploration of combination therapies. Overexpression of or CCK signaling is implicated in gastrointestinal malignancies, including gastric and pancreatic cancers, underscoring their trophic potential.

Secretin family

The secretin family comprises structurally related peptides that play key roles in gastrointestinal (GI) and pancreatic regulation, including , , glicentin, (VIP), gastric inhibitory polypeptide (GIP), and (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 , 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. and GIP are primarily produced in the , glucagon and glicentin derive from proglucagon processing in pancreatic α-cells and intestinal L-cells, while VIP is synthesized in enteric neurons. Secretin, a 27-amino-acid released from duodenal S-cells in response to luminal acidity, inhibits from parietal cells and stimulates bicarbonate-rich fluid from pancreatic ductal cells to maintain duodenal . , a 29-amino-acid , acts both endocrinely on the liver to promote and and paracrinely within to modulate insulin and , aiding local glucose regulation. VIP, a 28-amino-acid , relaxes GI smooth muscle and stimulates water and , facilitating coordinated and vasodilation. GIP, a 42-amino-acid from duodenal K-cells, potentiates glucose-dependent insulin release from pancreatic β-cells. Glicentin, a 69-amino-acid proglucagon-derived containing the full sequence, inhibits . 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 and downstream effectors. These peptides are regulated primarily through paracrine and autocrine mechanisms in the intestines and , with secretion triggered by luminal stimuli such as low pH for or nutrient ingestion (fats, carbohydrates, proteins) for GIP and glicentin. Neural inputs and hormonal feedback, including inhibition by , further modulate their release, ensuring coordinated postprandial responses. Degradation occurs rapidly via (DPP-4) and neutral endopeptidase, limiting their systemic and emphasizing local actions. Clinically, glucagon is administered to counteract severe hypoglycemia in diabetes management by rapidly mobilizing hepatic glucose stores. 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. In the 2020s, GIP's role has gained prominence through dual GIP/GLP-1 receptor agonists like , 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.

Eicosanoid Local Hormones

Prostaglandins

Prostaglandins are a class of lipid-derived local hormones known as , consisting of 20-carbon unsaturated s with a ring structure. They are primarily synthesized from the polyunsaturated arachidonic acid, which is released from cell membrane phospholipids. As local mediators, prostaglandins exert their effects primarily through on nearby cells due to their short biological half-life of 1 to 2 minutes. The biosynthesis of prostaglandins begins with the activation of , which liberates from membrane glycerophospholipids in response to cellular stimuli such as or . This free is then converted by the rate-limiting enzymes cyclooxygenase-1 (COX-1) and (COX-2) into the unstable endoperoxide intermediate (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 s or isomerases—such as prostaglandin E synthase for PGE2 or prostaglandin F for PGF2α—into distinct subtypes, which are then rapidly released to act locally. Prostaglandins play diverse roles in physiological and pathological processes, particularly in and . In , PGE2 promotes , enhances to facilitate immune cell infiltration, sensitizes nociceptors to amplify signaling, and acts on the to induce fever by raising the thermoregulatory set point. PGI2 contributes to regulating blood flow through in vascular and inhibits platelet aggregation to prevent excessive clotting, thereby maintaining vascular . In , PGF2α and PGE2 are critical for inducing and cervical ripening during labor; for instance, synthetic analogs like dinoprostone (PGE2) and (PGF2α) are used clinically to initiate labor. 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.

Leukotrienes

Leukotrienes are a class of local hormones derived from , distinct from prostaglandins in their biosynthesis pathway and primary roles in immune responses. These mediators are linear, 20-carbon chain molecules produced predominantly by leukocytes through the 5-lipoxygenase (5-LO) pathway. The pathway begins with the release of from membrane phospholipids by , followed by its oxygenation at the 5-position by 5-LO to form 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is then converted to (LTA4), the common precursor for all leukotrienes. Biosynthesis of leukotrienes requires the 5-lipoxygenase-activating protein (FLAP), an that facilitates the translocation of 5-LO to the and transfers to the , enabling efficient production at sites of . This process occurs rapidly in activated leukocytes, such as mast cells, , and macrophages, leading to the generation of dihydroxy (LTB4) from LTA4 via LTA4 hydrolase, or cysteinyl leukotrienes (LTC4, LTD4, LTE4) through sequential addition of and its derivatives by leukotriene C4 synthase and downstream enzymes. 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. LTB4 primarily functions as a potent chemoattractant, recruiting neutrophils to sites of and promoting their , , and superoxide production to enhance defenses. In contrast, cysteinyl leukotrienes (LTC4, LTD4, LTE4) mediate allergic and asthmatic responses by inducing through smooth muscle contraction in the airways, increasing to cause , and stimulating mucus hypersecretion, effects that are 100 to 1,000 times more potent than those of . These actions contribute to the pathophysiology of and , where elevated levels correlate with disease severity. Clinically, leukotrienes are targeted in asthma management with , a selective CysLT1 that blocks the effects of cysteinyl leukotrienes, reducing , airway , and exacerbations, particularly in patients with exercise-induced or allergic . In the 2020s, studies have linked dysregulated leukotriene production to cytokine storms in severe , where elevated LTB4 and cysteinyl leukotrienes exacerbate pulmonary and multi-organ damage, prompting investigations into leukotriene modifiers as adjunct therapies to mitigate hyper.

Other Local Hormones

Histamine and serotonin

is an amino acid-derived local hormone synthesized from L-histidine through by the L-histidine decarboxylase, utilizing pyridoxal-5’-phosphate as a cofactor. It is primarily stored in granules within mast cells and , where it associates with in mast cells and chondroitin-4-sulfate in . Upon stimulation, such as during allergic responses, these cells undergo , leading to rapid local release of that acts in a paracrine manner to influence nearby tissues. 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). Additionally, H1 receptor signaling contributes to bronchoconstriction and other immediate hypersensitivity symptoms. 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. 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. Serotonin, also known as 5-hydroxytryptamine (5-HT), is another local hormone derived from the L-tryptophan, converted via 1 (TPH1) in peripheral tissues. 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 (SERT). Upon triggers like mechanical stimulation or inflammation, serotonin is released locally from these stores, exerting paracrine effects through diffusion to adjacent cells. In the gut, serotonin promotes motility by activating 5-HT3 and 5-HT4 receptors on enteric neurons and , initiating and segmentation contractions essential for propulsion and mixing of contents. It also induces in submucosal arterioles via 5-HT2 receptors, regulating local flow and absorption. Furthermore, platelet-released serotonin facilitates aggregation and at sites of vascular injury, underscoring its role in local control. Serotonin's actions are mediated by seven families of G-protein-coupled receptors (5-HT1 to 5-HT7), along with the ionotropic , allowing diverse in tissues like the gut and vasculature. Both and serotonin function through rapid paracrine mechanisms, with release often triggered by or , 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. Clinically, H1 receptor antagonists (first- and second-generation antihistamines like diphenhydramine and loratadine) are first-line treatments for allergic conditions, blocking itching, , and symptoms, while H2 antagonists (e.g., ) reduce secretion in conditions like peptic ulcers. Selective serotonin reuptake inhibitors (SSRIs), such as , indirectly modulate local serotonin levels by inhibiting SERT, potentially altering gut motility and contributing to side effects like nausea or diarrhea in gastrointestinal disorders. Recent 2020s research highlights serotonin's role in the gut-brain axis, where enteric serotonin influences mood and cognition via interactions and vagal signaling, informing novel therapies targeting peripheral 5-HT pathways.

Kinins and angiotensin

Kinins are a class of local hormones generated through the enzymatic cleavage of kininogens by kallikreins, primarily producing and kallidin (also known as lysyl-). Kallidin is formed first and rapidly converted to by plasma aminopeptidase, with tissue and plasma kallikreins playing key roles in this activation process. These kinins act locally in a paracrine manner within vascular and inflammatory tissues, exerting effects on transmission, , and primarily through activation of B1 and B2 receptors. 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. Bradykinin, in particular, induces pain transmission by sensitizing nociceptors through B2 receptor activation, leading to in inflammatory conditions. It promotes in arteries and veins, such as those in the gut and , by stimulating release and relaxation. Additionally, kinins increase via both receptor types, facilitating plasma and formation during local inflammatory responses. 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 (ACE). Locally in tissues like the kidneys and adrenals, Ang II exerts paracrine effects, including of arterioles to regulate blood flow and pressure. It also stimulates aldosterone release from the zona glomerulosa, enhancing sodium reabsorption in the distal and contributing to . 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. Kinins bind B1/B2 receptors, triggering activation, intracellular calcium mobilization, and downstream pathways like MAPK for vascular and inflammatory signaling. Similarly, Ang II engages AT1 receptors to initiate Gq-protein coupling, hydrolysis, and , leading to and cellular proliferation. Clinically, the interplay between these systems is evident in management, where inhibitors block Ang II formation while accumulating kinins, enhancing but risking -mediated due to reduced degradation. elevation from inhibition contributes to this , characterized by non-pitting in subcutaneous tissues. Recent 2020s research highlights the local RAS's role in vascular damage, where downregulates ACE2, leading to unchecked Ang II accumulation, , and increased risk.

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