Molecular studies of CGRP and the CGRP family of peptides in the central nervous system

Abstract

Background Calcitonin gene-related peptide is an important target for migraine and other painful neurovascular conditions. Understanding the normal biological functions of calcitonin gene-related peptide is critical to understand the mechanisms of calcitonin gene-related peptide-blocking therapies as well as engineering improvements to these medications. Calcitonin gene-related peptide is closely related to other peptides in the calcitonin gene-related peptide family of peptides, including amylin. Relatedness in peptide sequence and in receptor biology makes it difficult to tease apart the contributions that each peptide and receptor makes to physiological processes and to disorders. Summary The focus of this review is the expression of calcitonin gene-related peptide, related peptides and their receptors in the central nervous system. Calcitonin gene-related peptide is expressed throughout the nervous system, whereas amylin and adrenomedullin have only limited expression at discrete sites in the brain. The components of two receptors that respond to calcitonin gene-related peptide, the calcitonin gene-related peptide receptor (calcitonin receptor-like receptor with receptor activity-modifying protein 1) and the AMY receptor (calcitonin receptor with receptor activity-modifying protein 1), are expressed throughout the nervous system. Understanding expression of the peptides and their receptors lays the foundation for more deeply understanding their physiology, pathophysiology and therapeutic use.

CGRP and Brain Functioning: Cautions for Migraine Treatment

“…Interestingly, peripheral (intraperitoneal) injection of CGRP is sufficient to elicit mild photophobia in mice, a central effect, although this may be from propagation of neural signaling rather than actual brain penetrance of CGRP . Alternatively, circulating CGRP may enter the brain at places such as the circumventricular organs, where the BBB is absent …”

“…The distribution of CGRP has been studied primarily in rats, where it is widespread throughout the brain. In particular, CGRP and/or its receptor have been found in the cortex, hippocampus, thalamus, hypothalamus, pituitary, striatum, amygdala, cerebellum, and such migraine‐relevant sites in the brainstem as the locus ceruleus, raphe nuclei, and the trigeminal nucleus caudalis …”

Novel Medications for the Treatment of Migraine

“…25 When activated during migraine, meningeal C-fibers release CGRP, which binds to receptors on trigeminovascular Aδ-fibers. 34 CGRP binds to both the canonical CGRP receptor and the AMY 1 receptor (CT receptor with RAMP1). 25 CGRP affects migraine pain through both central and peripheral sensitization, playing a role in vasodilation, plasma extravasation, neurogenic inflammation, mast cell degranulation, and regulation of gene expression.…”

Calcitonin Gene‐Related Peptide Antagonists in the Treatment of Episodic Migraine

“…There are two CGRP isoforms, α‐CGRP and β‐CGRP, differing by three amino acids but encoded by two distinct genes. They share similar biological properties but differ in regional potency and regulation . CGRP is found in many neural regions, including the trigeminal fibers, the neurons in TG, other sensory ganglia (e.g., dorsal root ganglia, jugular ganglia, etc.…”

“…RAMP facilitates the cell‐surface expression of CLR, and a change in RAMP function can alter the sensitivity to CGRP. Other combinations of different RAMPs or calcitonin/CLRs form receptors to amylin and adrenomedullin . RAMP1 favors CGRP as CGRP binds strongly to both the CGRP receptor and the AMY 1 receptor (formed by calcitonin receptor with RAMP1).…”