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Vasoactive intestinal peptide, also known as the vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a neuropeptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligand of class II G protein–coupled receptors. VIP is produced in many tissues of vertebrates including the gut, pancreas, and suprachiasmatic nuclei of the hypothalamus in the brain. VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. 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
Although the functional significance is not officially determined, the lead hypothesis points to the neurons using VIP to communicate with specific postsynaptic targets to regulate circadian rhythm [ref A1]. 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 VPAC2R. Another hypothesis supports VIP sending a paracrine signal from a distance rather than the adjacent postsynaptic neuron [ref A1].

VIP in the body
VIP has an effect on several tissues:
 * With respect to 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. Its role in the intestine is to greatly stimulate secretion of water and electrolytes, as well as relaxation of enteric smooth muscle, dilating peripheral blood vessels, stimulating pancreatic bicarbonate secretion, and inhibiting gastrin-stimulated gastric acid secretion. These effects work together to increase motility.
 * It also has the function of stimulating pepsinogen secretion by chief cells.
 * It is also found in the heart and has significant effects on the cardiovascular system. It causes coronary vasodilation as well as having a positive inotropic and chronotropic effect. 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.

VIP in the brain
It is also found in the brain and some autonomic nerves:
 * One region includes a specific area of the suprachiasmatic nuclei (SCN), the location of the 'master circadian pacemaker'.


 * The growth-hormone-releasing hormone (GH-RH) is a member of the VIP family and stimulates growth hormone secretion in the anterior pituitary gland [citation needed].
 * VIP helps to regulate prolactin secretion; it stimulates prolactin release in the domestic turkey.

Mechanisms
VIP binds to VPAC2 receptors, which triggers G-alpha-mediated signalling cascade. 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. The mPer1promoter 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 and Per2 in circadian rhythm [ref A3].

In addition, GABA levels are connected to VIP in that they are co-released. Sparse GABAergic connections are thought to decrease synchronized firing [ref A1]. 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 [ref A1].

Circadian time is likely to affect the synapses rather than the organization of VIP circuits [ref A1].

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. 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 [ref A2].

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. The neurons in this area receive retinal information from the retinohypothalamic tract and then relay the environmental information to the SCN [ref A1]. 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 [citation needed (from page)].

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 need for normal light induced synchronization of the circadian systems. 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 to 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 [ref A1].

Signaling pathway
In SCN, there is an abundant amount of VPAC2R. The presence of VPAC2R 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 [ref A2].

VIP and vasopressin are both important for neurons to relay information to different targets which will impose effect on neuroendocrine function. They transmit info through relay nuclei such as SPZ, DMH (dorsomedial nucleus of hypothalamus), MPOA (medial preoptic area) and PVN (paraventricular nucleus of hypothalamus) [ref A2].

[Additional reference to use for section: Maduna, 2016]

VIP receptors
There are two types of VIP receptors, VIPR1 and VIPR2. Both have high affinity to VIP, but need PACAP (pituitary adenylate cyclase-activating polypeptide) for binding. In the SCN, there are abundant amount of VPAC2R and its presence in ventrolateral portion suggests that VIP signals can actually signal back to regulate VIP secreting cells [ref A1].

VIPR1
VPAC1, The function of the VPAC1, or VIPR1, receptor [...] Gβγ release, Gs,i,q release from receptor [Waschek, 2013].

VIPR2
The VPAC2, or VIPR2, [not sure how much in depth to go here because the page exists; likewise with VIPR1]

Pathology
VIP is overproduced in VIPoma. Can be associated with Multiple Endocrine Neoplasia Type 1 (Pituitary, parathyroid and pancreatic tumors). Symptoms are typically:
 * Profuse non-bloody/non-mucoid diarrhea (3L+) causing dehydration and the associated electrolyte disturbances such as hypokalemia and metabolic acidosis.
 * Lethargy and exhaustion may ensue

Additional references

 * 1) Vasoactive intestinal peptide and the mammalian circadian system. Andrew M. Vosko, Analyne Schroeder, Dawn H. Loh, Christopher S. Colwell General and comparative endocrinology 152 (2007) 165-175 doi: 10.1016/j.ygcen.2007.04.018
 * 2) Properties of VIP+ synapses in the suprachiasmatic nucleus highlight their role in circadian rhythm. Nathan P. Achilly. Journal of Neurophysiology. 1 June 2016 Vol. 115 no. 6, 2701-2704 DOI: 10.1152/jn.00393.2015.
 * 3) Vasoactive intestinal peptide and the mammalian circadian system. Andrew M. Vosko, Analyne Schroeder, Dawn H. Loh, Christopher S. Colwell, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience, University of California—Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024-1759, USA.Received 19 September 2006, Revised 17 April 2007, Accepted 19 April 2007, Available online 26 May 2007. General and Comparative Endocrinology. Volume 152, Issues 2–3, June–July 2007, Pages 165–175.
 * 4) [more to be added]
 * 5) [more references are on the page and need to be added here]