Loss of Calcitonin Gene 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 CGRP's 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 CGRP's 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. Research 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 Gα-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.