Two specific amino acids in the first membrane segment of human vasoactive intestinal peptide receptors help maintain their active shape

Mutations at conserved tyrosine residues in VPAC(1) and VPAC(2) receptors significantly altered their affinity and potency for vasoactive intestinal polypeptide (VIP).

• Wild-type VPAC(1) receptors exhibited high affinity for VIP with an IC(50) of 1 nM, while the Y146A and Y150A mutants showed decreased affinity with IC(50) values of 30 nM and 4 nM, respectively.
• The Y130A and Y134A mutations in VPAC(2) receptors resulted in reduced potency for VIP, with EC(50) values of 200 and 400 nM compared to 7 nM for the wild-type receptor.
• [R(16)]-VIP acted as a 'super agonist' at both mutated VPAC(1) receptors, indicating altered receptor activation dynamics.
• VIP analogues modified at positions 1, 3, and 6 demonstrated significantly decreased efficacy at the mutated receptors compared to their wild-type counterparts.
• The findings suggest that the conserved tyrosine residues play a role in stabilizing the active conformation of the VPAC receptors rather than directly interacting with the key residues necessary for activation.

Simplified