Loss of Calcitonin gene-related Related Receptor component protein (RCP) in nervous system can bias gepant antagonism

We examined calcitonin gene-related peptide (CGRP)s effects on behavioral surrogates for motion-induced nausea and static imbalance in the nestinRCP (-/-), a novel mouse model that loses expression of receptor component protein (RCP) in the nervous system after tamoxifen induction. The assays used were the motion-induced thermoregulation and center of pressure (CoP) assays. Findings suggest CGRPs affects behavioral measures in the nestinRCP (-/-) similarly to littermate controls, since CGRP was observed to increase female sway and diminishes tail vasodilations to provocative motion in both sexes. However, the CGRP-receptor antagonist olcegepant did not antagonize CGRPs effects in the nestinRCP (-/-), whereas it was effective in littermate controls. Findings suggest RCP loss may change the sensitivity of the CGRP receptor and affect the efficacy of receptor antagonists. Significance StatementResearch in calcitonin gene-related peptide (CGRP) has primarily focused on ligand- receptor interactions at the calcitonin-like receptor (CLR) and receptor activity-modifying unit 1 (RAMP1) subunits. However, the role of receptor component protein (RCP), which mediates signaling via the G-stimulatory pathway, is less understood. A novel tamoxifen-inducible mouse model, nestinRCP (-/-), was generated to study loss of RCP in CGRP signaling in the nervous system, and behavioral changes to motion-induced nausea and postural sway were studied after systemic injections of CGRP or CGRP co-delivered with migraine drugs. Findings from this study suggest the loss of CGRP-RCP can bias "gepant" antagonists like olcegepant, and may promote development of therapies to inhibit the RCP-CLR interactions.