CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells

Abstract Agonist bias occurs when different ligands produce distinct signalling outputs acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate endogenous agonist with consequences for calcitonin receptor-like receptor, CLR. By switching receptor-activity modifying protein (RAMP) associated CLR can “re-route” pathways activated by agonists gene-related peptide (CGRP), adrenomedullin (AM) 2 (AM2). AM2 promotes calcium-mediated nitric oxide whereas CGRP AM show pro-proliferative effects in cardiovascular cells, thus providing a rationale expression of three peptides. CLR-based naturally has fundamental purpose existence. We anticipate this will be starting point more studies into RAMP function native environments their importance GPCR signalling.