Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a

peptide hormone Peptide hormones or protein hormones are hormones whose molecules are peptide, or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocrine system of animals, including h ...

that is

vasoactive A vasoactive substance is an endogenous agent or pharmaceutical drug that has the effect of either increasing or decreasing blood pressure and/or heart rate through its vasoactivity, that is, vascular activity (effect on blood vessels). By adju ...

in the intestine. VIP is a peptide of 28

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

residue Residue may refer to: Chemistry and biology * An amino acid, within a peptide chain * Crop residue, materials left after agricultural processes * Pesticide residue, refers to the pesticides that may remain on or in food after they are applied ...

s that belongs to a glucagon/secretin superfamily, the

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

of class II

G protein–coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

s. VIP is produced in many tissues of

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

s including the gut,

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...

, and

suprachiasmatic nuclei The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...

of the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

in the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

. VIP stimulates

contractility Contractility refers to the ability for self-contraction, especially of the muscles or similar active biological tissue *Contractile ring in cytokinesis *Contractile vacuole *Muscle contraction **Myocardial contractility *See contractile cell for ...

in the heart, causes

vasodilation Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...

, increases

glycogenolysis Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase. Mechanism The ...

, lowers arterial

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

and relaxes the smooth muscle of

trachea The trachea, also known as the windpipe, is a Cartilage, cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air-breathing animals with lungs. The trachea extends ...

, stomach and

gallbladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although ...

. In humans, the vasoactive intestinal peptide is encoded by the ''VIP''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. VIP has a

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...

(t_½) in the blood of about two minutes.

Function

In the body

VIP has an effect on several tissues: In the

digestive system The human digestive system consists of the gastrointestinal tract plus the accessory organs of digestion (the tongue, salivary glands, pancreas, liver, and gallbladder). Digestion involves the breakdown of food into smaller and smaller compone ...

, VIP seems to induce smooth muscle relaxation (

lower esophageal sphincter The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...

, stomach, gallbladder), stimulate secretion of water into

pancreatic juice Pancreatic juice is a liquid secreted by the pancreas, which contains a number of digestive enzymes, including trypsinogen, chymotrypsinogen, elastase, carboxypeptidase, pancreatic lipase, nucleases and amylase. The pancreas is located in the v ...

and

bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...

, and cause inhibition of

gastric acid Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the ...

secretion and absorption from the intestinal lumen. Its role in the intestine is to greatly stimulate secretion of water and

electrolytes An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon di ...

, as well as relaxation of enteric smooth muscle, dilating peripheral blood vessels, stimulating pancreatic bicarbonate secretion, and inhibiting

gastrin Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas. Gastrin ...

-stimulated gastric acid secretion. These effects work together to increase motility. It also has the function of stimulating

pepsinogen Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, whe ...

secretion by

chief cells In human anatomy, there are three types of chief cells, the gastric chief cell, the parathyroid chief cell, and the type 1 chief cells found in the carotid body. Cell types The gastric chief cell (also known as a zymogenic cell or peptic cell) is a ...

. VIP seems to be an important neuropeptide during inflammatory bowel diseases since the communication between mast cells and VIP in colitis, as in Crohn's disease, is upregulated. It is also found in the heart and has significant effects on the

cardiovascular system The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

. It causes coronary

as well as having a positive

inotropic An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction. The term ''inotro ...

and

chronotropic Chronotropic effects (from ''chrono-'', meaning time, and ''tropos'', "a turn") are those that change the heart rate. Chronotropic drugs may change the heart rate and rhythm by affecting the electrical conduction system of the heart and the ner ...

effect. Research is being performed to see if it may have a beneficial role in the treatment of

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

. VIP provokes

vaginal lubrication Vaginal lubrication is a naturally produced fluid that lubricates a vagina. Vaginal lubrication is always present, but production increases significantly near ovulation and during sexual arousal in anticipation of sexual intercourse. Vaginal dr ...

in normal women, doubling the total volume of lubrication produced.

In the brain

It is also found in the brain and some autonomic nerves: One region includes a specific area of the

(SCN), the location of the 'master

circadian A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

pacemaker'. See SCN and circadian rhythm below. VIP in the

pituitary In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypop ...

helps to regulate

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...

secretion; it stimulates prolactin release in the domestic turkey. Additionally, the growth-hormone-releasing hormone (GH-RH) is a member of the VIP family and stimulates

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...

secretion in the anterior pituitary gland.

Mechanisms

VIP binds to both VPAC1 and VPAC2 receptors. When VIP binds to VPAC2 receptors, a G-alpha-mediated signaling cascade is triggered. In a number of systems, VIP binding activates

adenyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

activity leading to increases in

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

and PKA. The PKA then activates other intracellular signaling pathways like the phosphorylation of

CREB CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...

and other transcriptional factors. The mPer1 promoter has CRE domains and thus provides the mechanism for VIP to regulate the molecular clock itself. Then it will activate gene expression pathways such as

Per1 The PER1 gene encodes the period circadian protein homolog 1 protein in humans. Function The PER1 protein is important to the maintenance of circadian rhythms in cells, and may also play a role in the development of cancer. This gene is a memb ...

and

Per2 PER2 is a protein in mammals encoded by the ''PER2'' gene. ''PER2'' is noted for its major role in circadian rhythms. Discovery The ''per ''gene'' ''was first discovered using forward genetics in '' Drosophilla melanogaster'' in 1971. Mammalia ...

in circadian rhythm. In addition, GABA levels are connected to VIP in that they are co-released. Sparse GABAergic connections are thought to decrease synchronized firing. While GABA controls the amplitude of SCN neuronal rhythms, it is not critical for maintaining synchrony. However, if GABA release is dynamic, it may mask or amplify synchronizing effects of VIP inappropriately. Circadian time is likely to affect the synapses rather than the organization of VIP circuits.

SCN and circadian rhythm

The SCN coordinates daily timekeeping in the body and VIP plays a key role in communication between individual

brain cell Brain cells make up the functional tissue of the brain. The rest of the brain tissue is structural or connective called the stroma which includes blood vessels. The two main types of cells in the brain are neurons, also known as nerve cells, an ...

s within this region. At a cellular level, the SCN expresses different electrical activity in circadian time. Higher activity is observed during the day, while during night there is lower activity. This rhythm is thought to be important feature of SCN to synchronize with each other and control rhythmicity in other regions. VIP acts as a major synchronizing agent among SCN neurons and plays a role in synchronizing the SCN with light cues. The high concentration of VIP and VIP receptor containing neurons are primarily found in the ventrolateral aspect of the SCN, which is also located above the

optic chiasm In neuroanatomy, the optic chiasm, or optic chiasma (; , ), is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrate ...

. The neurons in this area receive retinal information from the

retinohypothalamic tract In neuroanatomy, the retinohypothalamic tract (RHT) is a photic neural input pathway involved in the circadian rhythms of mammals. The origin of the retinohypothalamic tract is the intrinsically photosensitive retinal ganglion cells (ipRGC), whi ...

and then relay the environmental information to the SCN. Further, VIP is also involved in synchronizing the timing of SCN function with the environmental light-dark cycle. Combined, these roles in the SCN make VIP a crucial component of the mammalian

timekeeping machinery. After finding evidence of VIP in the SCN, researchers began contemplating its role within the SCN and how it could affect circadian rhythm. The VIP also plays a pivotal role in modulating oscillations. Previous pharmacological research has established that VIP is needed for normal light-induced synchronization of the circadian systems. Application of VIP also phase shifts the circadian rhythm of

vasopressin Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travel ...

release and neural activity. The ability of the population to remain synchronized as well as the ability of single cells to generate oscillations is composed in VIP or VIP receptor deficient mice. While not highly studied, there is evidence that levels of VIP and its receptor may vary depending on each circadian oscillation. The leading hypothesis of VIP function points to the neurons using VIP to communicate with specific postsynaptic targets to regulate

circadian rhythm A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...

. The depolarization of the VIP-expressing neurons by light appears to cause the release of VIP and co-transmitters (including GABA) that can in turn, alter the properties of the next set of neurons with the activation of VPAC2. Another hypothesis supports VIP sending a paracrine signal from a distance rather than the adjacent postsynaptic neuron.

Signaling pathway

In SCN, there is an abundant amount of VPAC2. The presence of VPAC2 in ventrolateral side suggests that VIP signals can actually signal back to regulate VIP secreting cells. SCN has neural multiple pathways to control and modulate endocrine activity. VIP and vasopressin are both important for neurons to relay information to different targets and affect neuroendocrine function. They transmit information through such relay nuclei as the SPZ (subparaventricular zone), DMH (

dorsomedial hypothalamic nucleus The dorsomedial hypothalamic nucleus is a nucleus of the hypothalamus. It is involved in feeding, drinking, body-weight regulation and circadian activity. More specifically, it is a necessary component for the expression of numerous behavioral a ...

), MPOA (medial

preoptic area The preoptic area is a region of the hypothalamus. MeSH classifies it as part of the anterior hypothalamus. TA lists four nuclei in this region, (medial, median, lateral, and periventricular). Functions The preoptic area is responsible for ther ...

) and PVN (

paraventricular nucleus of hypothalamus The paraventricular nucleus (PVN, PVA, or PVH) is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller ...

Social behavior

VIP neurons located in the hypothalamus, specifically the dorsal anterior hypothalamus and ventromedial hypothalamus, have an effect on social behaviors in many species of vertebrates. Studies suggest that VIP cascades can be activated in the brain in response to a social situation that stimulates the areas of the brain that are known to regulate behavior. This social circuit includes many areas of the hypothalamus along with the

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...

and the

ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...

. The production and release of the neuropeptide VIP is centralized in the hypothalamic and extrahypothalamic regions of the brain and from there it is able to modulate the release of prolactin secretion. Once secreted from the pituitary gland, prolactin can increase many behaviors such as parental care and aggression. In certain species of birds with a knockout VIP gene there was an observable decrease in overall aggression over nesting territory.

Pathology

VIP is overproduced in

VIPoma A VIPoma or vipoma () is a rare endocrine tumor that overproduces vasoactive intestinal peptide (thus ''VIP'' + '' -oma''). The incidence is about 1 per 10,000,000 per year. VIPomas usually (about 90%) originate from the non-β islet cells of ...

. In addition to VIPoma, VIP has a role in

osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...

(OA). While there is existing conflict in whether down-regulation or up-regulation of VIP contributes to OA, VIP has been shown to prevent cartilage damage in animals.

References

External links

Pathway at biocarta.com
* * {{Neuropeptides Peptide hormones Hormones of the digestive system Hormones of the hypothalamus Hormones of the hypothalamic-pituitary-prolactin axis