Target Validation Information
Target ID T86364
Target Name Vasoactive intestinal polypeptide receptor 1
Target Type
Clinical Trial
Drug Potency against Target Vasoactive intestinal peptide Drug Info IC50 = 1 nM [553229]
VIP Drug Info IC50 = 4.9 nM [529569]
Action against Disease Model Vasoactive intestinal peptide We performed the studies on the Kir6.1/SUR2B channel expressed in HEK293 cells. We found that the channel was strongly activated by VIP. Through endogenous VIP receptors, the channel activation was reversible and dependent on VIP concentrations with the midpoint-activation concentration approximately 10 nM. The channel activation was voltage-independent and could be blocked by KATP channel blocker glibenclamide. In cell-attached patches, VIP augmented the channel open-state probability with modest suppression of the single channel conductance. The VIP-induced Kir6.1/SUR2B channel activation was blocked by PKA inhibitor RP-cAMP. Forskolin, an adenylyl cyclase activator, activated the channel similarly as VIP. The effect of VIP was further evident in the native tissues. In acutely dissociated mesenteric vascular smooth myocytes, VIP activated the KATP currents in a similar manner as in HEK293 cells. In endotheli uM-free mesenteric artery rings, VIP produced concentration-dependent vasorelaxation that was attenuated by glibenclamide. [552742] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Disruption of the PAC1 receptor in mice results in impaired insulin secretion after Pituitary adenylate cyclase-activating peptide administration. However, these mice also display reduced glucose-stimulated insulin secretion following both oral and intravenous glucose administration,which suggests that the PAC1 receptor are important for the effect of glucose. Furthermore, VPAC2-/- mice exhibit reduced insulin secretion but maintained glucose tolerance after intravenous administration of glucose, suggesting peripheral effects on insulin sensitivity. [553229]
References
Ref 553229Vasoactive intestinal peptide (VIP)1 receptor. Three nonadjacent amino acids are responsible for species selectivity with respect to recognition of peptide histidine isoleucineamide. J Biol Chem. 1996 May 31;271(22):12795-800.
Ref 552742PKA-dependent activation of the vascular smooth muscle isoform of KATP channels by vasoactive intestinal polypeptide and its effect on relaxation of the mesenteric resistance artery. Biochim Biophys Acta. 2008 Jan;1778(1):88-96. Epub 2007 Sep 12.
Ref 529569J Med Chem. 2008 Jul 24;51(14):4150-69. Epub 2008 Jun 28.Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.

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