CRFR2 is a G-protein coupled receptor for CRF (corticotropin-releasing factor) and urocortins UCN1, UCN2, and UCN3. The receptor-ligand interaction causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase, leading to increased intracellular cAMP levels¹.

CRFR2 is expressed in the CNS and peripheral tissues including the heart, vasculature, skeletal muscle, and gastrointestinal tract, and it plays a central role in coordinating endocrine, autonomic, and behavioral responses to stress¹. CRFR2 ligands, the UCN peptides, exert actions in central and peripheral tissues where they modulate cardiovascular, immune, gastrointestinal, and reproductive functions in response to stress². UCNs can also affect tumor biology as a consequence of the CRFR2 role as a suppressor of vascularization³.

The involvement of CRF/UCN family peptides and their receptors in diverse pathophysiological states has generated intense interest in developing therapeutic agents that selectively target the receptors. CRFR2-selective agonists have the potential to treat heart failure⁴, hypertension⁵ and other disorders.

CRFR2 shares 68% amino acid sequence identity with another CRF receptor, CRFR1. Both of the receptors have a bipartite domain structure consisting of an N-terminal extracellular domain (ECD) of about 100–150 amino acids linked to a 7-transmembrane helical bundle domain embedded in the plasma membrane. Peptide binding spans the two domains, with the C-terminal portion of the peptide binding to the ECD to impart high affinity and the N-terminal portion binding to the 7-transmembrane domain to activate the receptor⁶.

CRFR2 has three functional full-length isoforms, α, β, and γ, that differ only at the extreme N-terminus of the receptor. In humans, the CRFR2β isoform is expressed in the brain, and the CRFR2α isoform predominates in the periphery⁶.