CALCRL (Calcitonin receptor-like receptor, CRLR) is a G protein-coupled receptor that binds CGRP (calcitonin gene-related peptide) and ADM (adrenomedullin) in complex with RAMP proteins. RAMP-CALCRL complexes binding either of these peptides activate cyclic AMP signaling. In nerve cells, CALCRL is involved in a CGRP cascade that can suppress the immune response and the recruitment of neutrophils in clean injuries, a process that can be counter-productive in cases of necrotizing fasciitis or unclean wounds. CGRP itself is involved in pain signal transmission, pain-induced threat memory, taste memory and appetite regulation in neurons in the central nervous system, and antagonists to both CGRP and its receptor CALCRL are of interest in migraine therapies. In immunohistochemistry, CALCRL has membranous and cytoplasmic positivity in all tissues, including the microvascular endothelium. References: Cell. 2018 May 17;173(5):1083-1097.e22, PMID: 29754819; Current Protein & Peptide Science. 14 (5): 386–92, PMID: 23745702; Cell. 2018. 41(5): 280-293, DOI: 10.1016/j.tins.2018.03.007; J Clin Pathol. 2004 Feb; 57(2): 172–176, PMID: 14747444; J Biol Chem. 2005 Mar 11;280(10):9297-307, PMID: 15613468;