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Modulation of CGRP‐receptor function by G‐protein βγ subunits

Activated CGRP–receptors (CGRP‐R) might relax vascular smooth muscle (VSM) via activation of Gsα and by inducing dissociation of endothelin‐1 (ET‐1) from ETA‐receptors (Meens et al. PLos ONE 2010). The latter “terminator effect” is not mimicked by other stimuli of Gsα. Thus, we analyzed roles of G‐protein βγ subunits (Gβγ) in CGRP‐R function. Organ chamber studies with rat arteries and radioligand binding studies on membranes from CHO cells expressing human CGRP‐R were performed. In several types of arteries, isoproterenol (ISO), forskolin and CGRP caused relaxation during K+‐induced contractions. The effects of CGRP did not correlate with those of ISO or forskolin. In mesenteric arteries, contracted with K+‐ or ET‐1, IBMX increased relaxations induced by sodium nitroprusside (SNP) or ISO, but not by CGRP. Gallein and M119 (Gβγ inhibitors), but not fluorescein (negative control), inhibited the relaxing effect and the “terminator effect” of CGRP while not altering arterial effects of i) K+, ii) ET‐1, iii) SNP or iv) ISO. Gallein did not displace [125I]‐CGRP from CGRP‐R but caused an acute fivefold increase of the Bmax for [125I]‐CGRP. In conclusion, activated CGRP‐R cause cyclic nucleotide‐independent relaxation of VSM and terminate arterial effects of ET‐1 via Gβγ. Also, Gβγ seems to restrict agonist‐binding to CGRP‐R.