Peptides

Peptides

Endogenous peptides and proteins include well characterized families of neuropeptide transmitters, neuropeptide modulators, hormones, and fragments of functional proteins, which are essential in many biological processes. The peptides exert potent biological actions in virtually all systems in the body (see figure for examples).

 

Pharmaceutical products which mimic the effects of endogenous peptide ligands are call peptidomimetics. Some examples of peptidomimetics and their corresponding endogenous ligand include desmopressin – vasopressin, octreotide – somatostatin, and insulin glargine – insulin. Drugs which block the receptors for endogenous peptide ligands can be peptide or non-peptide molecules. Examples include naloxone (opioid receptors), aprepitant (substance P receptors), and losartan (angiotensin II type 1).

Pharmacology of proteins and peptides

This 60-slide slide set available from Slideshare.net provides a good overview of endogenous peptides and select examples of useful drugs. Drugs discussed include those that mimic the effects of endogenous peptides and those that are antagonists. This slide set is appropriate as an introduction to the topic of peptide ligands. Authored by Rohan Kolla, PG in MD Pharmacology.

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Gastrointestinal peptides

The gastrointestinal hormones constitute a group of hormones secreted by enteroendocrine cells in the stomach, pancreas, and small intestine. This group of hormones regulate various functions of the digestive organs. Some of the major families are listed below.

 

Gastrointestinal peptides, their site(s) of expression and major functions.

Hormone or peptide Major tissue locations in the gut Principal known actions
Bombesin: neuromedin B, gastrin releasing peptide Throughout the gut and pancreas Stimulate release of cholecystokinin (CCK) and gastrin
Calcitonin gene-related peptide: α-CGRP, β-CGRP Enteric nerves Unclear
Chromogranin A Neuroendocrine cells Secretory protein
Enkephalins Stomach, duodenum Opiate-like actions
Enteroglucagon Small intestine, pancreas Inhibits insulin secretion
Galanin Enteric nerves Unclear
Ghrelin Stomach Stimulates appetite, increases gastric emptying
Glucagon-like peptide 1 Pancreas, ileum Increases insulin secretion
Glucagon-like peptide 2 Ileum, colon Enterocyte-specific growth hormone
Growth factors Throughout the gut Cell proliferation and differentiation
Growth hormone-releasing hormone Small intestine Unclear
Leptin Stomach Appetite control
Motilin Throughout the gut Increases gastric emptying and small bowel motility
Neuropeptide Y Enteric nerves Regulation of intestinal blood flow
Neurotensin Ileum Affects gut motility; increases jejunal and ileal fluid secretion
Pancreatic polypeptide Pancreas Inhibits pancreatic and bilary secretion
Peptide YY Colon Inhibits food intake
Somatostatin: SRIF-28, SRIF-14 Stomach, pancreas Inhibits secretion and action of many hormones
Substance P Enteric nerves Unclear
Trefoil peptides: trefoil factor 1, trefoil factor 2, trefoil factor 3 Stomach, intestine Mucosal protection and repair

 

 

 

This regularly up-dated webpage provides a synopsis of the synthetic processes involved in production of gastrointestinal peptides, and regulation of these processes. Therapeutic implications are also briefly discussed.

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The gastrointestinal hormones constitute a group of hormones secreted by enteroendocrine cells in the stomach, pancreas, and small intestine. This group of hormones regulate various functions of the digestive organs. Some of the major families are listed below.

 

Gastrointestinal peptides, their site(s) of expression and major functions.

Hormone or peptide Major tissue locations in the gut Principal known actions
Bombesin: neuromedin B, gastrin releasing peptide Throughout the gut and pancreas Stimulate release of cholecystokinin (CCK) and gastrin
Calcitonin gene-related peptide: α-CGRP, β-CGRP Enteric nerves Unclear
Chromogranin A Neuroendocrine cells Secretory protein
Enkephalins Stomach, duodenum Opiate-like actions
Enteroglucagon Small intestine, pancreas Inhibits insulin secretion
Galanin Enteric nerves Unclear
Ghrelin Stomach Stimulates appetite, increases gastric emptying
Glucagon-like peptide 1 Pancreas, ileum Increases insulin secretion
Glucagon-like peptide 2 Ileum, colon Enterocyte-specific growth hormone
Growth factors Throughout the gut Cell proliferation and differentiation
Growth hormone-releasing hormone Small intestine Unclear
Leptin Stomach Appetite control
Motilin Throughout the gut Increases gastric emptying and small bowel motility
Neuropeptide Y Enteric nerves Regulation of intestinal blood flow
Neurotensin Ileum Affects gut motility; increases jejunal and ileal fluid secretion
Pancreatic polypeptide Pancreas Inhibits pancreatic and bilary secretion
Peptide YY Colon Inhibits food intake
Somatostatin: SRIF-28, SRIF-14 Stomach, pancreas Inhibits secretion and action of many hormones
Substance P Enteric nerves Unclear
Trefoil peptides: trefoil factor 1, trefoil factor 2, trefoil factor 3 Stomach, intestine Mucosal protection and repair

 

 

 

A regularly updated and peer reviewed webpage summarising the role of GI peptides in health and disease, with links to additional webpages covering other relevant topics, e.g. physiology of gastrin, ghrelin, pancreatic polypeptide, peptide YY, and neuropeptide Y, insulin action and physiology of somatostatin and its analogues.

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Neuropeptides

Neuropeptides are small proteinaceous cell-cell signaling molecules produced and released by neurons. They differ from peptide hormones in that they are secreted from neurons and act locally on neighbouring neurons, whereas peptide hormones are secreted in to the blood by neuroendocrine cells and act at distant sites. Neuropeptides are the most diverse class of signaling molecules in the brain, and are involved in a broad range of brain functions, including analgesia, reproduction, learning and memory, reward, food intake and more. Characteristics relevant to neuropeptide function are 1) their secretion is through a 'regulated' route, 2) they are not recycled once secreted and 3) they may be modified in the extracellular space by peptidases which can either inactivate their biological activity or conversely, increase target binding affinity.

Neuropeptides often co-exist with other neurotransmitters in defined cell populations, but are contained in separate storage vesicles. Neuropeptides are held within large dense-core vesicles (LDCVs) throughout the cell body, whereas neurotransmitters are contained in small vesicles located at synapses.

In humans there are ~90 genes encoding neuropeptide precursors, which are processed to ~100 bioactive neuropeptides.

This is an internet resource compiling data about all known neuropeptides, their genes, precursors and expression in the brain.

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Endocrine peptides

Endocrine peptides are the proteinaceous subset of the hormones produced by the glands of the endocrine system. The major endocrine glands include the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid gland, parathyroid gland, hypothalamus, gastrointestinal tract and adrenal glands. Endocrine hormones regulate a vast array of bodily functions including metabolism, growth and development, tissue function, sexual function, reproduction, sleep, and mood.

The table below provides details of the endocrine glands, the hormones they secrete and some of the principal effects of the hormones. Non-peptide hormones are shown in italics for clarity.

Endocrine organ Secreted hormone(s) Effect(s)
Hypothalamus thyroid-releasing hormone (TRH) stimulates release of TSH from anterior pituitary
dopamine inhibits prolactin release from anterior pituitary
growth hormone-releasing hormone (GHRH) stimulates GH release from anterior pituitary
somatostatin inhibits release of GH and TSH from anterior pituitary
gonadotropin-releasing hormone (GnRH) stimulates release of FSH and LH from anterior pituitary
cortocotropin-releasing hormone (CRH) stimulates ACTH release from anterior pituitary
vasopressin increases water permeability in distal convoluted tubule: increases blood volume
Pineal gland melatonin regulates circadian rhythm
Pituitary gland- anterior growth hormone (GH)-somatotrophs stimulates growth and cell proliferation; stimulates hepatic insulin-like growth factor 1 release
thyroid-stimulating hormone (TSH)- thyrotrophs stimulates thyroxine (T4) and triiodothyronine (T3) synthesis and release from thyroid gland; stimulates iodine uptake by thyroid gland
adrenocorticotropic hormone (ACTH)- corticotrophs stimulates corticosteroid (glucocorticoid and mineralcorticoid) and androgen synthesis and release from adrenocortical cells
beta endorphin- corticotrophs inhibits pain sensation
follicle-stimulating hormone (FSH)- gonadotrophs stimulates ovarian follicle maturation in females; stimulates maturation of seminiferous tubules, spermatogenesis and production of androgen-binding protein in males
luteinizing hormone (LH)- gonadotrophs stimulates ovulation and formation of corpus luteum in females; stimulates testosterone synthesis from Leydig cells (interstitial cells) in males
prolactin (PRL)- lactotrophs stimulates milk synthesis and release from mammary glands; mediates sexual gratification
melanocyte-stimulating hormone (MSH)- melanotrophs stimulates melanin synthesis and release from melanocytes in hair and skin
Pituitary gland- posterior oxytocin- magnocellular neurosecretory cells stimulates uterine contraction during labour; stimulates the letdown reflex in nursing mothers
vasopressin (ADH or AVP)- parvocellular neurosecretory neurons increases water permeability in distal convoluted tubule: increases blood volume
Thyroid gland T3-thyroid epithelial cells more potent form of thyroid hormone- increases basal metabolic rate; stimulates protein synthesis
T4- thyroid epithelial cells pro-hormone for T3- same effects
calcitonin- parafollicular cells reduces blood calcium; stimulates bone formation
GI tract-stomach gastrin- G cells stimulates secretion of gastric acid by parietal cells
ghrelin- P/D1 cells increases appetite
neuropeptide Y (NPY) increases food intake
somatostatin- D cells suppresess release of gastrin, cholecystokinin (CCK), secretin, motilin, vasoactive intestinal peptide (VIP), gastric inhibitory polypeptide (GIP), enteroglucagon; slows gastric emptying; reduces smooth muscle contraction and blood flow in intestine
histamine- ECL cells stimulates gastric acid secretion
endothelin- X cells regulates smooth muscle contraction in stomach
GI tract-duodenum secretin- S cells regulates secretion of bicarbonate from liver, pancreas and Brunner's gland (duodenum); enhances effects of CCK, stops gastric juice production
cholecystokinin (CCK)- I cells promotes release of digestive enzymes from pancreas and release of bile from the gall bladder; hunger suppressant
GI tract-liver insulin-like growth factor 1 (somatomedin, IGF)- hepatocytes insulin-like effects; regulates growth and development
angiotensinogen- hepatocytes vasoconstriction; stimulates release of aldosterone from adrenal cortex
angiotensin- hepatocytes vasoconstriction; stimulates release of aldosterone from adrenal cortex
thrombopoietin (THPO)- hepatocytes stimulates megakaryocytes to produce platelets in the bone marrow
hepcidin- hepatocytes inhibits intestinal iron absorption and iron release by macrophages
GI tract-pancreas insulin- β islet cells stimulates glucose absorption from blood to skeletal muscles and fat tissue; promotes fat storage; inhibits hepatic glucose production
glucagon- α islet cells increases blood glucose level; stimulates glycogenolysis and gluconeogenesis in liver
somatostatin- δ islet cells inhibits insulin and glucagon release; inhibits exocrine secretion from pancreas
pancreatic polypeptide- PP cells modulates hepatic glycogen levels and gastrointestinal secretions; auto-regulates pancreatic secretion
Kidney renin- juxtaglomerular cells stimulates the renin-angiotensin system by producing angiotensin I from angiotensinogen
erythropoietin- extraglomerular mesangial cells stimulates erythrocyte production
calcitrol (active form of vitamin D3) stimulates absorption of calcium and phosphate from GI tract and kidneys; inhibits release of parathyroid hormone
thrombopoietin stimulates megakaryocytes to produce platelets in the bone marrow
Adrenal glands- cortex

 

glucocorticoids- zona fasciculata and zona reticularis cells stimulate gluconeogenesis; stimulates fat breakdown in adipose tissue; inhibit protein synthesis and glucose uptake in muscle and adipose tissue; immunosuppressive; anti-inflammatory
mineralocorticoids- zona glomerulosa cells stimulate active sodium reabsorption and passive water reabsorption in kidneys (increasing blood volume and pressure); stimulate renal potassium and H+ excretion
androgens: DHEA and testosterone- Zona fasciculata and Zona reticularis cells masculising effects in females; in males, effects are insignificant compared to those elicited by testicular androgens
Adrenal glands- medulla adrenaline- chromaffin cells promotes mechanisms underlying the fight-or-flight response e.g. boosting oxygen and glucose supplies to the brain and muscles, increasing heart rate and stroke volume, increasing hepatic glycogen catalysis, and suppressing non-emergency bodily-proceses
noradrenaline- chromaffin cells promotes mechanisms underlying the fight-or-flight response e.g. boosting oxygen and glucose supplies to the brain and muscles, increasing heart rate and stroke volume, increasing hepatic glycogen catalysis
dopamine- chromaffin cells increases heart rate and blood pressure
enkephalin- chromaffin cells regulates pain
Reproductive organs- testes androgens- Leydig cells anabolic effects; virulizing
estradiol- sertoli cells prevents apoptosis of germ cells
inhibin- sertoli cells inhibits FSH production
Reproductive organs- ovarian follicle and corpus luteum progesterone- granulosa cells, theca cells supports pregnancy
androstendione- theca cells metabolic precursor of both testosterone and estrone
estrogens (mainly estradiol)- granulosa cells promotes development of secondary female sex characteristics; stimulates endometrial growth
inhibin- granulosa cells inhibits FSH production
Reproductive organs- pregnant placenta progesterone supports pregnancy; inhibits onset of labour and lactation; supports fetal mineralo- and glucocorticosteroid production
estrogens effects on mother similar to ovarian follicle-derived estrogen
human chorionic gonadotropin (hCG)- syncytiotrophoblast promotes maintenance of the corpus luteum at the beginning of pregnancy; suppresses the immune response to the developing embryo
human placental lactogen-syncytiotrophoblast increases insulin and IGF-1 production; increases insulin resistance and carbohydrate intolerance
inhibin- fetal trophoblasts inhibits FSH production
Reproductive organs- pregnant uterus prolactin (PRL)- decidual cells stimulates milk production in mammary glands
relaxin- decidual cells relaxes the ligaments in the pelvis and softens and widens the cervix
Parathyroid gland parathyroid hormone (PTH)- parathyroid chief cells increases the concentration of ionic calcium (Ca2+) in the blood; decreases serum phosphate; promotes renal activation of vitamin D
Skin calcidiol (25-hydroxyvitamin D, inactive form of vitamin D3)  
Heart atrial-natriuretic peptide (ANP)- cardiac myocytes reduces blood pressure
brain natriuretic peptide (BNP)- cardiac myocytes reduces blood pressure
Skeletal muscle myokines  
Adipose tissue leptin- adipocytes appetite suppressant; increases metabolic rate
estrogens (mainly estrone)- adipocytes