Different Vasoactive Intestinal Polypeptide Receptor Domains Are Involved in the Selective Recognition of Two VPAC2-Selective Ligands

Nov 26, 1999Molecular pharmacology

Different parts of the VIP receptor help recognize two molecules that specifically target the VPAC2 receptor

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Abstract

C(6)-VIP acted as a high-affinity agonist for certain receptor chimeras.

C(6)-VIP showed preferential binding to VPAC(2) receptors compared to VIP.
The binding profile indicated that Ro 25-1553's high affinity for VPAC(2) is influenced by the amino-terminal domain.
Chimeric receptors demonstrated that VIP had reduced affinity when combined with VPAC(1) and VPAC(2) sequences.
C(6)-VIP maintained high-affinity binding on chimeric receptors modified from VPAC(1) and VPAC(2).
Certain antagonists displayed comparable affinities for both wild-type and chimeric receptors, suggesting proper folding but inactivity in achieving high-affinity states.

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A vasoactive intestinal polypeptide (VIP) analog, acylated on the amino-terminal histidine by hexanoic acid (C(6)-VIP), behaved as a VPAC(2) preferring agonist in binding and functional studies on human VIP receptors, and radioiodinated C(6)-VIP was a suitable ligand for binding studies on wild-type and chimeric receptors. We evaluated the properties of C(6)-VIP, its analog AcHis(1)-VIP, and the VPAC(2)-selective agonist Ro 25-1553 on the wild-type VPAC(1) and VPAC(2) receptors and on the chimeric receptors exchanging the different domains between both receptors. VIP had a normal affinity and efficacy on the chimeras starting with the amino-terminal VPAC(2) receptor sequence. The binding and functional profile of these chimeric receptors suggested that the high affinity of Ro 25-1553 for VPAC(2) receptors is supported by the amino-terminal extracellular domain, whereas the ability to prefer C(6)-VIP over VIP is supported by the VPAC(2) fifth transmembrane (TM5)-EC(3) receptor domain. These results further support the hypothesis that the central and carboxyl-terminal regions of the peptide (modified in RO 25-1553) recognize the extracellular amino-terminal region domain, whereas the amino-terminal VIP amino acids bind to the TM receptor core. VIP had a reduced affinity and efficacy on the N-VPAC(1)/VPAC(2) and on the N-->EC(2)-VPAC(1)/VPAC(2) chimeric receptors. C(6)-VIP behaved as a high-affinity agonist on these constructions. The antagonists [AcHis(1),D-Phe(2),Lys(15),Arg(16), Leu(27)]VIP(3-7)/GRF(8-27) and VIP(5-27) had comparable affinities for the wild-type receptors and for the two latter chimeras, supporting the hypothesis that these chimeras were properly folded but unable to reach the high-agonist-affinity, active receptor conformation in response to VIP binding.

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Different Vasoactive Intestinal Polypeptide Receptor Domains Are Involved in the Selective Recognition of Two VPAC2-Selective Ligands

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