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Vasoactive intestinal peptide (VIP) is a 28-amino-acid polypeptide that belongs to the glucagon/secretin superfamily. It is the ligand of class II/class B secretin receptor-like G protein–coupled receptors VPAC1 and VPAC2. VIP is synthesized in multiple brain areas and is broadly distributed in both the central and peripheral nervous systems of vertebrates and is released from nerve terminals that innervate numerous organs, including urogenital and gastrointestinal tracks, heart, lung, kidney, and thyroid. It is active in immune organs like spleen, thymus, bone marrow, and lymph nodes. Its wide distribution reflects its many roles as a neurotransmitter, vasodilator, and immune modulator. VIP also serves as a signaling factor between suprachiasmatic nucleus (SCN) neurons in the brain, serving as a master mammalian circadian clock synchronizer. In humans, the vasoactive intestinal peptide is encoded by the VIP gene.

VIP has a half-life (t½) in the blood of about two minutes.

Function
VIP has many functions in the body, including smooth muscle relaxation, vasodilation, stimulation of secretion, and regulation of circadian rhythms. 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.

Function in the body
VIP has an effect on several tissues:

In the digestive system, VIP seems to induce smooth muscle relaxation (lower esophageal sphincter, stomach, gallbladder), stimulate secretion of water into pancreatic juice and bile, and cause inhibition of gastric acid secretion and absorption from the intestinal lumen. In the intestine, VIP stimulates the secretion of water and electrolytes. It also relaxes enteric smooth muscle, dilates peripheral blood vessels, stimulates pancreatic bicarbonate secretion, and inhibits gastrin-stimulated gastric acid secretion. These effects combine to contribute to the peristaltic or wavelike contractions of the intestine, also known as intestinal motility. VIP also acts to stimulate pepsinogen secretion by chief cells. VIP appears to interact with some 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, where it causes coronary vasodilation and has positive inotropic and chronotropic effects. Research is being performed to see if it may have a beneficial role in the treatment of heart failure. VIP provokes vaginal lubrication in normal women, doubling the total volume of lubrication produced.

Function in the brain
VIP 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 pacemaker'. See SCN and circadian rhythm below. VIP in the pituitary helps to regulate prolactin 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 secretion in the anterior pituitary gland.

In the cortex, VIP neurons play an important role in the local regulation of metabolism in the cerebral cortex by stimulating glycogenolysis and altering cortical blood flow. VIP also helps to modulate cortical blood flow through its vasodilatory properties.

Mechanisms
VIP is an agonist for both VPAC1 and VPAC2 receptors. When VIP binds to VPAC2 receptors, a G-alpha-mediated signalling cascade is triggered. In a number of systems, VIP binding activates adenyl cyclase activity leading to increases in cAMP and PKA. The PKA then activates other intracellular signaling pathways like the phosphorylation of CREB and other transcriptional factors.

SCN and circadian rhythm
The SCN coordinates daily timekeeping in the body and VIP plays a key role in communication between individual brain cells within this region. As cellular oscillators, SCN cells express different electrical activities in circadian time (the quantification of time as defined by an organism's endogenous circadian clock, without reference to any environmental regularities or zeitgebers). Higher activity is observed during the day, while during night there is lower activity. This rhythm is an important feature of the SCN, as the cells synchronize with each other and control rhythmicity in other regions.

GABA is co-released with VIP, contributing to the synchronization of the SCN cells through inhibition. 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.

VIP acts as a major synchronizing agent among SCN neurons and plays a role in synchronizing the SCN with light cues. In VIP KO mice that lack the peptide, there is a loss of circadian rhythms in cellular [Ca2+]i  and CRE-dependent transcription across the SCN due to a lack of synchrony between individual neurons. Influx of cellular calcium is necessary for the SCN polarization that initiates the CRE-dependent cell photoentrainment or synchronization. The amplitude and synchrony of the rhythms can be restored in vitro through a wild-type SCN graft, where VIP from healthy cells interacts with VIP KO cells in a paracrine fashion. This transfusion demonstrates that VIP is necessary for circadian rhythm synchrony.

The dampened rhythms of VIP KO mice are consistent with behavioral studies where VIP-/- and VPAC2-/- mice express much weaker circadian rhythms as a result of many SCN neurons being in different phase. This loss of rhythmicity and synchrony leads to a signal that is much less clear and robust. The highest concentration of VIP and VIP receptor(VPAC2) containing neurons are primarily found in the ventrolateral aspect of the SCN, which is also located above the optic chiasm. The neurons in this area receive retinal information from the retinohypothalamic tract 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 circadian timekeeping machinery.

The VIP also plays a pivotal role in modulating oscillations. SCN neurons exhibit a daily rhythm of electrical activity with high activity during the day and low activity at night. It was found that VIP- and VPAC2R-deficient mice fail to exhibit the aforementioned midday peak in electrical activity. Single cell imaging of these mice indicated that fewer cells were rhythmic and that the normal synchrony of mPer1 expression in the SCN was lost in the Vipr2−/−mice. VIP has also been theorized to modulate transcriptional oscillation of clock genes. When Vipr2−/− mice were crossed with mice carrying either the mPer1::luciferase or mPer1::GFP transgenes, SCN slice cultures displayed low levels of mPer1 expression without the robust circadian variation seen in the controls. Furthermore, when VPAC2R-deficient mice were placed in constant dim red light, expression of mPer1, mPer2, mCry1 and mBmal1 was uniformly low and arrhythmic in the SCN, while WT controls exhibited robust rhythms.

Previous pharmacological research has established that VIP is needed for normal light-induced synchronization of the circadian systems. VIP KO mice fail to shift their behavioral rhythms in response to a phase-delaying light pulse during early subjective night. Furthermore, VIP−/− and VPAC2−/− mice display activity advanced by 8-10 hours when they are placed in constant darkness (DD). Their period is 22.5 hrs compared to the WT’s 23.5 hours, and many of the knockout mice eventually become arrhythmic in DD. Interestingly, when exposed to a skeleton photoperiod -- an external light-dark cycle in which a long period of light (the day phase) is not present, and instead short periods of light mark the beginning and end of the day phase -- consisting of two light pulses per cycle, VIP deficient animals exhibit two discrete activity bouts, as opposed to a singular discrete activity bout in the WT.

Application of VIP also phase shifts the circadian rhythm of vasopressin 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.

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. VIP utilizes paracrine signaling over a long time frame and wide spatial domain. Different mutant grafts onto VIP-null SCN cells all resulted in restored cell synchrony with the same rhythmicity of the grafted mutant even without direct contact between neurons. The SCN has neural multiple neural and hormonal pathways to control and modulate endocrine activity. The SCN controls daily rhythms of hormone secretion. In some instances, SCN neurons make direct synaptic connections with neurosecretory neurons. In other instances, SCN signals set the phase of "clock genes" that regulate circadian function at the cellular level within neurosecretory cells. The protein products of these clock genes can also exert direct transcriptional control over neuroendocrine releasing factors. Finally, the SCN signals endocrine glands via the autonomic nervous system, allowing for rapid regulation via multisynaptic pathways.

VIP and vasopressin are both important for neurons to relay information to different targets and affect neuroendocrine function. Evidence has shown that VIP/VPAC2R regulates inhibitory synaptic transmission. Individual cells within the SCN oscillate with different phases, and application of GABA, a predominantly inhibitory neuropeptide, can synchronize these cellular oscillators. This GABA-mediate mechanism has been theorized to explain the loss of synchrony observed in VIP- and VPAC2R- deficient mice. Electrophysiological experiments characterizing GABAA-mediated spontaneous inhibitory post-synaptic currents (sIPSCs) have found that VIP is a potent modulator of GABA-mediated synaptic transmission within the SCN. This VIP regulation of inhibitory synaptic transmission appears to be responsible for driving a circadian rhythm in GABA-mediated synaptic transmission. This is consistent with findings that other hypothalamic neuropeptides have the ability to prime vesicle stores for activity-dependent release.They transmit information through such relay nuclei as the SPZ (subparaventricular zone), DMH (dorsomedial hypothalamic nucleus), MPOA (medial preoptic area) and PVN (paraventricular nucleus of hypothalamus).

PACAP
VIP shows high homology (~68%) to Pituitary adenylate-cyclase-activating polypeptide (PACAP). They share two common G-protein coupled receptors: the VPAC1-Receptor (VPAC1-R) and VPAC2-Receptor (VPAC2-R).

PDF
The neuropeptide pigment dispersing factor (PDF) is a functional homolog of VIP in insects. In Drosphilia, the PDF is expressed in a subset of lateral circadian pacemaker neurons implicated in driving locomotor activity rhythms (e.g. anticipatory activity of sunrise). Flies without PDF lose this ability to anticipate the onset of light. Pacemaker cells in flies lose the ability to regulate the timing of PER and TIM entry into the nucleus in flies without PDF. PDF knockouts also result in dampened behavior, a shortened period, and 70% of the flies eventually becoming arrhythmic. The knockout results in a lack of synchrony between different cell groups, dampened molecular oscillations, and loss of rhythmicity in transcription and protein activity - similar to VIP knockouts.

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 and the ventral tegmental area. 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.

In addition to VIPoma, VIP has a role in osteoarthritis (OA). Dysregulation of bone homeostasis due to a lack of the regulatory sympathetic innervation of immunoreactive VIP neurons in close proximity to the bone cells during development. While there is existing conflict in whether down-regulation or up-regulation of VIP contributes to OA, as stimulation and inhibition of the sympathetic nervous system show anabolic and catatonic effects, VIP has been shown to prevent cartilage damage in animals.