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).
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 | |
| corticotrophin-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 mineralocorticoid) 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 | suppresses 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-processes |
| 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 |
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.
- Gastrin–cholecystokinin family: gastrin (gastrin-34,”big gastrin”; gastrin-17, “little gastrin”; gastrin-14, “minigastrin”) and cholecystokinin (CCK-58, CCK-33, CCK-22 and CCK-8)
- Secretin family: secretin, glucagon, vasoactive intestinal peptide and gastric inhibitory peptide
- Somatostatin family: SRIF-28 (= somatostatin), SRIF-14
- Substance P
- Ghrelin, a growth hormone secretagogue synthesised by endocrine cells in the stomach, stimulates gastrointestinal motility like motilin agonists
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 biliary 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.
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.
RESOURCES
This is an internet resource compiling data about all known neuropeptides, their genes, precursors and expression in the brain.
Pharmacology of Proteins and Peptides
RESOURCES
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.
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.