Loss of Calcitonin Gene Related Receptor component protein (RCP) in nervous system can bias "gepant" antagonism

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Calcitonin gene-related peptide (CGRP) signaling is crucial, but the role of receptor component protein (RCP) is not fully understood.
• Existing research on CGRP primarily focuses on calcitonin-like receptor (CLR) and RAMP1 interactions.
• RCP mediates signaling through the Gα-stimulatory pathway, making its function in CGRP pathways significant.

Purpose of the Study:

• To investigate the effects of CGRP on behavioral responses related to motion-induced nausea and static imbalance.
• To analyze these effects in a novel nestinRCP (-/-) mouse model with induced loss of RCP in the nervous system.
• To evaluate the efficacy of CGRP receptor antagonists in the absence of RCP.

Main Methods:

• Generation of a tamoxifen-inducible nestinRCP (-/-) mouse model to study RCP loss in the nervous system.
• Utilized motion-induced thermoregulation and center of pressure (CoP) assays to assess behavioral surrogates.
• Administered CGRP and CGRP with the antagonist olcegepant to both knockout and control mice.

Main Results:

• CGRP affected behavioral measures, including increased sway in females and diminished tail vasodilation in both sexes, similarly in nestinRCP (-/-) mice and controls.
• The CGRP antagonist olcegepant failed to antagonize CGRP's effects in nestinRCP (-/-) mice.
• Olcegepant remained effective in littermate controls, indicating a differential response in the absence of RCP.

Conclusions:

• Loss of RCP in the nervous system may alter CGRP receptor sensitivity and the efficacy of CGRP receptor antagonists.
• These findings suggest that RCP plays a critical role in modulating CGRP signaling pathways.
• Targeting RCP-CLR interactions could offer a novel therapeutic strategy for conditions involving CGRP signaling.