CALCRL


Calcitonin receptor-like, also known as the calcitonin receptor-like receptor, is a human protein; it is a receptor for calcitonin gene-related peptide.

Tissue distribution

RNA expression charts show highest expression in lung and adipose tissue in humans. Cell types that express the highest levels of CALCRL include oligodendrocyte precursor cells, endothelial cells, lymphatic endothelial cells, adipocytes, endometrial stromal cells, as well as dendritic cells.

Structure

The calcitonin receptor-like protein is a class B G protein-coupled receptor characterized by seven transmembrane helices and a relatively large N-terminal extracellular domain comprising 100–160 residues and three conserved disulfide bonds. CALCRL forms functional heterodimeric complexes with one of three single transmembrane receptor activity-modifying proteins, namely RAMP1, RAMP2, or RAMP3, which determine its ligand specificity. The extracellular domain of CALCRL consists of one α-helix, two antiparallel β-strands, five loop regions, and is stabilized by intramolecular disulfide bonds, which are crucial for ligand binding and specificity. The CALCRL/RAMP complex presents a unique ligand-binding pocket, enabling selective recognition of peptide agonists on the extracellular surface, which then triggers conformational changes in transmembrane helices to facilitate intracellular G-protein coupling and signal transduction.

Function

The protein encoded by the CALCRL gene is a G protein-coupled receptor related to the calcitonin receptor. CALCRL is linked to one of three single transmembrane domain receptor activity-modifying proteins that are essential for functional activity.
The association of CALCRL with different RAMP proteins produces different receptors:
  • with RAMP1: produces a CGRP receptor
  • with RAMP2: produces an adrenomedullin receptor, designated AM1
  • with RAMP3: produces a dual CGRP/AM receptor designated AM2
These receptors are linked to the G protein Gs, which activates adenylate cyclase and activation results in the generation of intracellular cyclic adenosine monophosphate.
CGRP receptors are found throughout the body, suggesting that the protein may modulate a variety of physiological functions in all major systems.
The CGRP family of receptors including CALCRL can couple to G-protein Gαs, Gαi and Gαq subunits to transduce their signals. Furthermore binding of ligands to CALCRL can bias coupling to these G-protein. Peptide agonist bind to the extracellular loops of CALCRL. This binding in turn causes TM5 and TM6 to pivot around TM3 which in turn facilitates Gαs binding.

Adrenomedullin receptor

CALCRL binds Ramp2 to form the adrenomedullin receptor 1, while it binds Ramp3 to form adrenomedullin receptor 2. Adrenomedullin is a multifunctional 52 amino acid peptide widely expressed throughout the body. Its most prominent functions include regulation of blood pressure, endothelial barrier development and stability, and inflammation. Administration of adrenomedullin causes vasodilation and decreased blood pressure via binding to its receptors.

Clinical significance

s are FDA approved for the treatment of migraine. This includes Erenumab, Ubrogepant and Zavegepant.

Wounds

In wounds, CGRP receptors found in nerve cells deactivate the immune system, to prevent collateral damage in case of a clean wound. In very preliminary research, nerve blockers like e.g. lidocaine or botox have been demonstrated to block CGRP cascade, thereby allowing immune system involvement and control of pathogens, resulting in complete control and recovery.