PAC1 Receptor

Abstract

Septic shock is a systemic response to severe bacterial infections, generally caused by Gram-negative bacterial endotoxins, with multiple manifestations such as hypotension, tissue injury, disseminated intravascular coagulation, and multi-organ failure. All these effects, are induced by the generation of pro-inflammatory and vasodilator mediators, cell adhesion molecules, coagulation factors, and acute-phase proteins. Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two immunopeptides with anti-inflammatory properties exerted through type 1 and 2 VIP receptors (VPAC1 and VPAC2, respectively), and PACAP receptor (PAC1). The present results recapitulate the protective role of PAC1 in an experimental model of lethal endotoxemia using a knockout for the PAC1 receptor. Our results demonstrate that VIP and PACAP decrease lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) production, neutrophil infiltration and intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and fibrinogen expression through PAC1 receptor, providing an advantage to design more specific drugs complementing standard intensive care therapy in septic shock.

A functional polymorphism of the vasoactive intestinal peptide receptor 1 gene correlates with the presence of HLA-B *2705 in Sardinia

“…26 Accordingly, VIP has been reported to protect mice from lethal endotoxemia, presumably by downregulating endogenous pro-inflammatory macrophage-derived mediators, 27 to inhibit the production of several pro-inflammatory cytokines [28][29][30][31] and chemokines such as IL-8, 26 and to exert a protective effect in some models of autoimmune diseases. [5][6][7][8][9][10] It has been speculated that the suppressive effect on VIPR1 transcription can be mediated by a cis-regulatory repressor element located on the gene. Pei cloned a repressor protein that downes VIPR1 expression in rats, 32 however, a homologous VIPR1 repressor protein in humans has not been identified as yet.…”

“…3,4 Accordingly, VIP has been described as an effective therapeutic agent in several animal models of inflammatory/autoimmune diseases, such as inflammatory bowel disease, collagen-induced arthritis, experimental autoimmune encephalomyelitis, endotoxic shock, Parkinson's disease and Sjogren's disease. [5][6][7][8][9][10] However, its translation to the clinic and its application in the corresponding human diseases is still far off.…”

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…Both PACAP and VIP inhibit neutrophil chemotaxis in vitro and in vivo (Kinhult et al, 2001b(Kinhult et al, , 2002Martínez et al, 2005). In a model of septic shock, PACAP reduces leukocyte infiltration in target organs and induces a decrease of the mRNA encoding the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (Martínez et al, 2002(Martínez et al, , 2006. In spleen cells, PACAP inhibits the expression of IP-10 (CXCL10) but stimulates the expression MDC (CCL22), two chemokines attracting Th1 and Th2 cells, respectively, leading thereby to the preferential recruitment of the antiinflammatory Th2 cell population (Delgado et al, 2002b;Jiang et al, 2002).…”

The selective PAC1 receptor agonist maxadilan inhibits neurogenic vasodilation and edema formation in the mouse skin

“…The anti-inflammatory actions of VIP are well-known, however, relatively little is reported regarding its involvement in neurogenic inflammation. Evidence has accumulated over the last decade that VPAC1 receptor is primarily responsible for the anti-inflammatory actions of VIP and PACAP in experimental arthritis and Crohn's disease, while PAC1R was found to mediate the protective effects against septic endotoxemia (Abad et al, 2003;Delgado et al, 2000Delgado et al, , 2001Martinez et al, 2006). Involvement of VPAC1/2 receptors was also reported in pressure-induced vasodilation, a process associated with the activation of capsaicin-sensitive nerve fibers and CGRP-release (Fizanne et al, 2004).…”