Calcitonin Gene—Related Peptides and Neuromuscular Interactions

Calcitonin gene-related peptide (CGRP) was initially discovered by the analysis of the gene coding for calcitonin and of its transcription products.] The genomic domain that includes the structural gene for calcitonin is composed of six exons that are alternatively spliced to yield calcitonin mRNA in thyroid C cells and a novel peptide CGRP in the neurons of the central and peripheral nervous system. Calcitonin mature mRNA is produced by splicing the first three exons to the fourth, accompanied by the cleavage polyadenylation at the 3’ end of the fourth exon; CGRP mature mRNA, on the other hand, results from the splicing of the first three exons to the fifth and sixth exon using the distal poly(A) site 3‘ to the sixth exon (Rosenfeld et ul., this volume). Since the discovery of CGRP, two other genes encoding CGRP-like peptides have been identified in rat and man. The latter two genes, on the other hand, encode only one protein: the precursor protein of PCGRP or an islet amyloid protein (amylin) (Jansz et al. and Bennett and Amara, this volume). P-CGRP, differs from the original a-CGRP by one amino acid in rats and by three amino acids in humans.?-’The functional difference in the two different forms of CGRP is unknown. CGRP-like immunoreactivity has been detected in several endocrine tissues and in a large number of cell groups and pathways in the central nervous system (Hokfelt et al. this volume). The mRNAs encoding aand P-CGRP can be specifically differentiated by nucleic acid hybridization. CGRP is mostly present in enteric autonomous neuron^,^ but both sensory ganglia and motor neurons express both forms of CGRP.’ aand P-CGRP thus belong to the wide category of neuropeptides known to coexist with classical neurotransmitters in vertebrate central nervous system6 This short review is focused on a possible role of CGRP as a communication signal between motor neurons and skeletal muscle. The role of CGRP is not viewed like that of a classical transmitter, such as acetylcholine, which is directly engaged in the production of electrical signals in the postsynaptic cells. Rather, CGRP will be considered as a slow-acting “trophic” or “modulatory” factor engaged, in particular, in the regulation of postsynaptic acetylcholine receptor and/ or efficacy.9