A receptor map for one of the better-characterised systems in the catalog, and what it changes about reading the papers.
In short
- VIP was isolated from small intestine by Said and Mutt in 1970. PACAP was isolated from sheep hypothalamus by Miyata, Arimura and colleagues in 1989.
- PACAP's N-terminal sequence is 68% identical to VIP's, and in rat pituitary cells it stimulated adenylate cyclase at least a thousand times more potently.
- Three receptors were cloned between 1992 and 1993. Two of them, now VPAC1 and VPAC2, respond to both peptides; the third, PAC1, strongly prefers PACAP.
- PAC1 splice variants couple differently to adenylyl cyclase and phospholipase C, so the same peptide can signal differently in different tissues.
Two isolations, nineteen years apart
Vasoactive intestinal peptide was found by what it did to blood vessels. Said and Mutt reported in Science in 1970 that they had isolated a polypeptide from small intestine with broad biological activity, vasodilation foremost, and it was later sequenced as a 28-residue peptide. For its first decade it was studied mainly as a gut hormone; its role as a neurotransmitter in central and peripheral neurons came later.
Pituitary adenylate cyclase-activating polypeptide was found by what it did to a second messenger. Miyata, Arimura and colleagues, reporting in Biochemical and Biophysical Research Communications in 1989, purified a 38-residue peptide from ovine hypothalamus by following cyclic-AMP production in cultured rat anterior pituitary cells. Its N-terminal sequence was 68% identical to VIP's, but its adenylate cyclase activity in that assay was at least a thousand times greater. A shorter 27-residue form was identified soon after.
The authors were explicit about what they did not know: the peptide increased release of several pituitary hormones from superfused cells at very low concentrations, but whether that was its primary physiological role was left open. Twenty years on, Vaudry and colleagues' review in Pharmacological Reviews describes a peptide with roles well beyond the pituitary.
Cloning the receptors
The receptors arrived within about eighteen months of each other, and all three belong to the class B G-protein-coupled receptor family alongside the receptors for secretin, glucagon and calcitonin.
Ishihara and colleagues in Osaka cloned the first VIP receptor from a rat lung library, reporting in Neuron in 1992. It bound VIP and stimulated adenylate cyclase when expressed in cultured cells, and its mRNA was found widely in rat brain neurons, with relatively high expression in cerebral cortex and hippocampus. This is the receptor now called VPAC1.
Lutz, Harmar and colleagues in Edinburgh cloned a second, reporting in FEBS Letters in 1993. Expressed in COS-7 cells, it produced cyclic AMP in response to VIP and to both forms of PACAP with equal potency; its mRNA sat mainly in thalamus, hippocampus and the suprachiasmatic nucleus. They called it the VIP2 receptor; it is now VPAC2.
Spengler and colleagues in Montpellier isolated the third by expression cloning, reporting in Nature in 1993. This one, the type I PACAP receptor and now PAC1, was specific for PACAP. Both PACAP forms stimulated adenylyl cyclase through it at sub-nanomolar concentrations, but only PACAP-38 stimulated phospholipase C potently.
Splice variants, and why one peptide can signal two ways
Spengler's group did not stop at one PAC1 sequence. They isolated four further splice variants with insertions in the third intracellular loop, the region that couples a receptor to its G proteins, and found that each altered the balance between adenylyl cyclase and phospholipase C signalling.
That is a mechanism for the same ligand producing different intracellular responses depending on which variant a cell expresses, and it is one reason the PACAP literature resists simple summary. A result in one tissue does not transfer automatically to another, even within the same species.
What this changes about reading VIP research
Harmar and colleagues consolidated the naming in IUPHAR Review 1 in the British Journal of Pharmacology in 2012: VPAC1 and VPAC2 respond to VIP and PACAP with similar affinity, while PAC1 has far higher affinity for PACAP than for VIP. Each receptor has its own tissue distribution and its own selective tool compounds.
The practical consequence is about attribution. A VIP effect reported in a tissue could run through VPAC1, VPAC2, or both, and older papers written before the receptors were cloned often cannot say which. A PACAP effect could additionally involve PAC1. Where a study used selective agonists, antagonists or receptor-knockout animals, the receptor can be named; where it did not, the honest reading is that the peptide had an effect and the receptor is unassigned.
This is also why VIP is a useful contrast to less-characterised compounds elsewhere in the Neurobiology world. The questions are sharper because the pieces are named.
The limits
VIP is listed in the catalog for laboratory research. It is not an approved drug in the United States, nothing here describes an effect in a person, and none of it is a protocol. The neuropeptides article covers VIP's place alongside the ACTH-fragment compounds and DSIP.
References
- Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169(3951):1217–1218.
- Miyata A, Arimura A, Dahl RR, et al.. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochemical and Biophysical Research Communications. 1989;164(1):567–574.
- Ishihara T, Shigemoto R, Mori K, et al.. Functional expression and tissue distribution of a novel receptor for vasoactive intestinal polypeptide. Neuron. 1992;8(4):811–819.
- Lutz EM, Sheward WJ, West KM, et al.. The VIP2 receptor: molecular characterisation of a cDNA encoding a novel receptor for vasoactive intestinal peptide. FEBS Letters. 1993;334(1):3–8.
- Spengler D, Waeber C, Pantaloni C, et al.. Differential signal transduction by five splice variants of the PACAP receptor. Nature. 1993;365(6442):170–175.
- Vaudry D, Falluel-Morel A, Bourgault S, et al.. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacological Reviews. 2009;61(3):283–357.
- Harmar AJ, Fahrenkrug J, Gozes I, et al.. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR Review 1. British Journal of Pharmacology. 2012;166(1):4–17.
What this article is, and is not
This is a summary of published research, written for qualified professionals evaluating compounds for laboratory work. Every compound discussed is supplied by strictly for in-vitro and laboratory research use. None is a drug, a dietary supplement, or a cosmetic; none is intended for human or veterinary use; and nothing above is medical advice, a treatment recommendation, or a claim that any compound produces any effect in a person. We publish no dosing or administration guidance of any kind.
