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Receptor Activity-Modifying Proteins Differentially Modulate the G Protein-Coupling Efficiency of Amylin Receptors

Drug Discovery Biology Laboratory (M.M., N.T., S.G.B.F., G.C., T.D.W., A.C., P.M.S.), Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia and Howard Florey Institute and Department of Pharmacology (M.M.), The University of Melbourne, Victoria 3010, Australia

Address all correspondence and requests for reprints to: Professor Patrick M. Sexton, Department of Pharmacology, Building 13E, Monash University, Wellington Road, Clayton, Victoria 3800, Australia. E-mail: patrick.sexton{at}med.monash.edu.au.

Receptor activity-modifying proteins (RAMPs) 1, 2, and 3 are prototypic G protein-coupled receptor accessory proteins that can alter not only receptor trafficking but also receptor phenotype. Specific RAMP interaction with the calcitonin receptor (CTR) generates novel and distinct receptors for the peptide amylin; however, the role of RAMPs in receptor signaling is not understood. The current study demonstrates that RAMP interaction with the CTRa in COS-7 or HEK-293 cells leads to selective modulation of signaling pathways activated by the receptor complex. There was a 20- to 30-fold induction in amylin potency at CTR/RAMP1 (AMY₁) and CTR/RAMP3 (AMY₃) receptors, compared with CTR alone, for formation of the second-messenger cAMP that parallels an increase in amylin binding affinity. In contrast, only 2- to 5-fold induction of amylin potency was seen for mobilization of intracellular Ca⁺⁺ or activation of ERK1/2. In addition, in COS-7 cells, the increase in amylin potency for Ca⁺⁺ mobilization was 2-fold greater for AMY₃ receptors, compared with AMY₁ receptors and this paralleled the relative capacity of overexpression of G_q proteins to augment induction of high affinity ¹²⁵I-amylin binding. These data demonstrate that RAMP-complexed receptors have a different signaling profile to CTRs expressed in the absence of RAMPs, and this is likely due to direct effects of the RAMP on G protein-coupling efficiency.