CRHR2

CRHR2 is the class B GPCR for urocortins 2 and 3 - the stress-responsive peptides that counterbalance CRHR1's anxiogenic HPA-axis drive with anxiolytic, cardiovascular-protective, and anorexigenic effects. While CRHR1 drives CRH-induced cortisol and ACTH release, CRHR2 is the receptor that terminates stress responding and restores homeostasis. It is expressed primarily in the heart, skeletal muscle, gastrointestinal tract, and brain lateral septum/hippocampus, and its selective ligands urocortin 2 and urocortin 3 bind with >1000-fold selectivity over CRHR1. Urocortin 2 IV infusion improved hemodynamics in Phase 2 heart failure trials. This card defines the scaffold space for stress-axis peptides that selectively engage peripheral CRHR2 without HPA activation.

CRHR2 (chromosome 7p14.3) produces three alternatively spliced isoforms: α (411 aa, predominant brain), β (431 aa, peripheral - heart, GI, skeletal muscle, lung), and γ (minor, human-specific). All isoforms share canonical class B GPCR architecture: N-terminal ECD (~100 aa, two β-sheets stabilized by disulfide bonds forming a shallow groove) → two-domain ligand binding → Gs/cAMP primary signaling. Urocortin 1 (Ucn1, 40 aa) binds both CRHR1 and CRHR2 with Ki ~0.3–0.6 nM; urocortin 2 (Ucn2, stresscopin-related peptide, 38 aa) binds CRHR2 with Ki ~0.66 nM and CRHR1 with Ki >100 nM; urocortin 3 (Ucn3, stresscopin, 38 aa) binds CRHR2 with Ki ~0.50 nM and CRHR1 with Ki >100 nM. CRH binds CRHR2 with Kd ~10–40 nM (10-fold weaker than CRHR1). CRHR2 selectivity for Ucn2/3 over CRH arises from a "selectivity filter": position 35 Ala in Ucn2/Ucn3 (vs. Arg in CRH) avoids charge repulsion with Pro100 of CRHR2 ECL; mutagenesis validates this contact. Crystal structures of CRHR2α ECD bound to Ucn1, Ucn2, Ucn3 (2.5–2.75 Å) show ligand C-terminal residues 26–41 in continuous α-helix anchored by Ile93/Lys92 hydrogen bonds and Tyr95/Ile47 hydrophobic pocket. Signaling: Gs → cAMP → PKA → cardiomyocyte protection, skeletal muscle glucose uptake, smooth muscle relaxation, anxiety attenuation; β-arrestin → MAPK (β-isoform in myometrium). CRHR2 knockout mice develop exacerbated heart failure, feeding dysregulation, and cardiovascular abnormalities - confirming protective roles. SNP rs2270007 associates with citalopram treatment resistance; rs4722999/rs3779250 associate with IBS susceptibility.

No CRHR2-targeted drug is approved. Urocortin 2 (IV infusion) showed improved cardiac hemodynamics (↓preload/afterload) in Phase 2 HF trials without significant chronotropy - proof of concept for the cardioprotective indication. Astressin2-B (cyclo(31-34)[D-Phe¹¹,His¹²,CαMeLeu¹³,³⁹,Nle¹⁷,Glu³¹,Lys³⁴]Ac-sauvagine(8-40)) is the selective CRHR2 antagonist research standard (IC₅₀ 1.3 nM at CRHR2, >500 nM at CRHR1, >100-fold selectivity, 6-hour in vivo duration). Antisauvagine-30 ([D-Phe¹¹,His¹²]sauvagine(11-40)) is a second selective antagonist tool. For peptide research, the tractable recipes are: Ucn2 C-terminal helix (residues 26–38) with lactam bridge cyclization at positions 31–34 to stabilize the active helical conformation for improved plasma stability; Ucn3 N-terminal truncations to define the minimum pharmacophore retaining CRHR2 selectivity; fatty acid–conjugated Ucn2 analogs for once-weekly SC dosing in chronic heart failure support; and CRHR2 agonist/GLP-1R agonist dual-peptide scaffolds exploiting their skeletal muscle co-expression to drive combined glucose uptake and CRHR2-mediated anabolic signaling.