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bioRxiv · 10.1101/2023.01.13.523955

Adrenomedullin 2/intermedin is a slow off-rate, long-acting endogenous agonist of theadrenomedullin2 G protein-coupled receptor

Babin, K. M.·Karim, J. A.·Gordon, P. H.·Lennon, J.·Dickson, A.·Pioszak, A. A.
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Abstract

The signaling peptides adrenomedullin 2/intermedin (AM2/IMD), adrenomedullin (AM), and CGRP have overlapping and distinct functions in the cardiovascular, lymphatic, and nervous systems by activating three shared receptors comprised of the class B GPCR CLR in complex with a RAMP1, -2, or -3 modulatory subunit. Here, we report that AM2/IMD, which is thought to be a non-selective agonist, is kinetically selective for CLR-RAMP3, known as the AM2R. AM2/IMD-AM2R elicited substantially longer duration cAMP signaling than the eight other peptide-receptor combinations due to AM2/IMD slow off-rate binding kinetics. The regions responsible for the slow off-rate were mapped to the AM2/IMD mid-region and the RAMP3 extracellular domain. MD simulations revealed how these bestow enhanced stability to the complex. Our results uncover AM2/IMD-AM2R as a cognate pair with unique temporal features, define the mechanism of kinetic selectivity, and explain how AM2/IMD and RAMP3 collaborate to shape the signaling output of a clinically important GPCR.

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Babin, K. M., Karim, J. A., Gordon, P. H., Lennon, J., Dickson, A., Pioszak, A. A.. 2023-01-13. Adrenomedullin 2/intermedin is a slow off-rate, long-acting endogenous agonist of theadrenomedullin2 G protein-coupled receptor. https://doi.org/10.1101/2023.01.13.523955

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