Two tyrosine residues in the first transmembrane helix of the human vasoactive intestinal peptide receptors play a role in supporting the active conformation

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.

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