Expression and function of calcitonin gene-related peptide (CGRP) receptors in trigeminal ganglia of R192Q Cacna1a knock-in mice

Neurosci Lett. 2016 May 4;620:104-10. doi: 10.1016/j.neulet.2016.03.046. Epub 2016 Mar 25.

Abstract

Migraine is a neurovascular brain disorder suggested to be due to dysfunction of the trigeminovascular system with sensitization of trigeminal ganglion (TG) nociceptors. Since the neuropeptide calcitonin gene-related peptide (CGRP) has been established as a key player in the pathogenesis of migraine, CGRP receptor antagonists have been considered useful compounds to block headache originating from hyperactivation of such TG neurons. Whereas there is some information on the expression of CGRP receptors in postmortem human tissue, data are lacking for migraineurs suffering from common or genetic migraine. To help to clarify these issues it is very useful to study a transgenic knock-in (KI) mouse model of hemiplegic migraine expressing a R192Q missense mutation in the α1 subunit of CaV2.1 calcium channels previously found in patients with familial hemiplegic migraine type-1 (FHM-1). The aim of the present study, therefore, was to compare CGRP receptor expression and function in wildtype (WT) versus KI mouse TG. The principal components of the CGRP receptor, namely the CLR and RAMP-1 proteins, were similarly expressed in WT and KI TG neurons (in situ or in culture) and responded to exogenous CGRP with a strong rise in cAMP concentration. Hence, the previously reported phenotype of sensitization of KI TG neurons is not due to up-regulation of CGRP receptors but is likely caused by a constitutively larger release of CGRP. This observation implies that, in FHM-1 TG, normal TG sensory neuron signaling can be restored once the extracellular concentration of CGRP returns to control level with targeted treatment.

Keywords: CGRP receptor; CLR; Familial hemiplegic migraine type-1; Nociception; RAMP1; cAMP.

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / pharmacology
  • Calcitonin Receptor-Like Protein / metabolism
  • Calcium Channels, N-Type / genetics*
  • Cells, Cultured
  • Cerebellar Ataxia / genetics
  • Gene Knock-In Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Migraine Disorders / genetics
  • Mutation, Missense
  • Neurons / metabolism
  • Primary Cell Culture
  • Receptor Activity-Modifying Protein 1 / metabolism
  • Receptors, Calcitonin Gene-Related Peptide / metabolism*
  • Trigeminal Ganglion / metabolism*

Substances

  • Calcitonin Receptor-Like Protein
  • Calcium Channels, N-Type
  • Calcrl protein, mouse
  • Ramp1 protein, mouse
  • Receptor Activity-Modifying Protein 1
  • Receptors, Calcitonin Gene-Related Peptide
  • voltage-dependent calcium channel (P-Q type)
  • Calcitonin Gene-Related Peptide

Supplementary concepts

  • Hemiplegic migraine, familial type 1