RAMP1

RAMP1, or receptor activity-modifying protein 1, is a single-pass transmembrane protein encoded by the RAMP1 gene and part of the RAMP family (RAMP1-3) that regulate a subset of class B G protein-coupled receptors. RAMP proteins do not signal themselves; instead, they associate with certain GPCRs to alter trafficking to the cell surface and determine ligand specificity.

Most notably, RAMP1 associates with the calcitonin receptor-like receptor (CLR). The CLR–RAMP1 complex forms the canonical receptor for calcitonin gene-related peptide (CGRP), with high affinity for CGRP. When CLR associates with RAMP2 or RAMP3, different receptor specificities emerge, while RAMP1 can also associate with the calcitonin receptor (CTR) to form amylin receptors (AMY1).

Structurally, RAMP1 is a type I transmembrane protein with an extracellular N-terminus that interacts with CLR, a single transmembrane helix, and a cytoplasmic tail that participates in intracellular trafficking and receptor regulation.

Physiologically, CLR–RAMP1 signaling mediates CGRP-induced vasodilation and nociception; CGRP receptor signaling is implicated in migraine pathophysiology. RAMP1 expression patterns influence receptor distribution across tissues, including the nervous system and vasculature, shaping CGRP responsiveness in different organs.

Clinically, CGRP receptors are prominent targets in migraine therapy. Because RAMP1 determines CGRP receptor formation and pharmacology, it is integral to the action of CGRP antagonists and antibodies. Alterations in RAMP1–CLR interactions can modulate CGRP signaling and may have broader implications for vascular and nociceptive functions.