VIP/PACAP GPCR Assays

Background of VIP/PACAP Receptors

The pituitary adenylate-cyclase-activating polypeptide (PACAP) is a neuropeptide that belongs to the vasoactive intestinal polypeptide (VIP)/glucagon/secretin family. The high homology between PACAP and VIP allows them to share three common G protein-coupled receptors (GPCRs), including PAC1 receptor (PAC1R), VPAC1 receptor (VPAC1R), and VPAC2 receptor (VPAC2R). PACAP and its receptors are involved in a variety of biological functions in the peripheral and central nervous systems.

Fig.1. Molecular mechanism of VIP signal transduction. (Tang, 2014)

Distributions and Functions of VIP/PACAP Receptors

VPAC1R is distributed widely in the CNA, liver, lung, intestine, and T-lymphocytes, while the expression of VPAC2R can be detected in CNS, pancreas, skeletal muscle, heart, kidney, adipose tissue, testis, and stomach. PAC1R is predominantly expressed in the CNS, adrenal medulla, and pancreas. These receptors bind to both VIP and PACAP for further biological functions.

Subtypes and Mechanisms of VIP/PACAP Receptors

Based on their affinity for PACAP and VIP, PAC1R is classified into type 1 receptors, while VPAC1R and VPAC2R are classified into type II receptors, respectively.

Receptor	Gene	Mechanism	Agonists	Antagonists
Vasoactive intestinal peptide receptor 1	VIPR1	Vasoactive intestinal peptide receptor 1 is associated with AC through cAMP, and activates PKA and the mitogen-activated protein kinase (MAPK) pathway.	VIP	VIP (6-28) [D-p-Cl-Phe⁶,Leu¹⁷]-VIP PG97-269
Vasoactive intestinal peptide receptor 2	VIPR2	Vasoactive intestinal peptide receptor 2 is associated with AC through cAMP, and activates PKA and the mitogen-activated protein kinase (MAPK) pathway.	Bay 55-9837 VIP	VIP (6-28) [D-p-Cl-Phe⁶,Leu¹⁷]-VIP PACAP6-38
ADCYAP receptor type I	ADCYAP1R1	ADCYAP receptor type 1 is associated with AC through cAMP, and activates PKA and the mitogen-activated protein kinase (MAPK) pathway. ADCYAP receptor type 1 couples to phospholipase C to stimulate Ca²⁺ mobilization and protein kinase C activation.	PACAP 1-27 PACAP 1-38	PA 8 PACAP 6-38

Published Data

Paper Title	Signal Transduction by VIP and PACAP Receptors
Journal	Biomedicines
Published	2022
Abstract	The homeostasis of the human immune system is regulated by two neuropeptides, VIP and PACAP. These two neuropeptides can regulate intestinal motility and secretion, and affect the function of the endocrine & immune systems. Inhibition of VIP and PACAP receptors has therefore been investigated for new drug therapies in chronic inflammation and cancer. In this paper, we describe VPAC1, VPAC2, and PAC1 as triggers for receptor activation and compare them to similar noncovalent interactions observed for other GPCRs upon activation. The interaction between VIP and PACAP receptors provides a molecular basis for the development of anti-inflammatory, anti-cancer, and neuroprotective drugs. In addition, we also examined the effect of genetic variants of VIP, PACAP, and their receptors on endogenous agonist-mediated signaling.
Result	VIP and PACAP receptor signaling is of high complexity. The weak selectivity of endogenous agonists has somewhat hampered the therapeutic application of VPAC and PAC1 receptors in endocrine, metabolic, anti-inflammatory, and anticancer treatments. Recently, the discovery of the first small-molecule negative allosteric modulator provides new ideas for drug repositioning screening. The cryo-EM structures of VPAC1 and PAC1 also provided a conformational basis. In this paper, we have verified that the VIP/PACAP receptor signaling pathway was associated with the regulation of excessive inflammatory responses and provided a new approach for the treatment of chronic autoimmune diseases and acute inflammation. Fig.2. VIP and PACAP receptor-mediated signaling pathways. (Langer, et al., 2022)

References

Tang, B.; et al. Vasoactive intestinal peptide receptor-based imaging and treatment of tumors. International journal of oncology. 2014, 44(4): 1023-1031.
Langer, I.; et al. Signal transduction by VIP and PACAP receptors. Biomedicines. 2022, 10(2): 406.

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