Target Background

The corticotropin-releasing hormone receptor 2 (CRHR2) is a class B G-protein-coupled receptor (GPCR) that, together with CRHR1, mediates the actions of the corticotropin-releasing hormone (CRH) family of neuropeptides. CRHR2 is distinctively expressed in peripheral tissues such as the heart, skeletal muscle, and gastrointestinal tract, with additional expression in specific brain regions including the lateral septum, hypothalamus, and medial amygdala. Its tissue distribution reflects its primary role in modulating the recovery phase of the stress response, promoting adaptive behaviors, and regulating energy homeostasis.

Upon binding to its preferred ligands—urocortin 2 (Ucn2) and urocortin 3 (Ucn3)—CRHR2 couples predominantly to Gs proteins, stimulating adenylate cyclase and elevating intracellular cAMP levels, similar to CRHR1. However, the contrasting physiological outcomes arise from its distinct expression pattern. In the brain, CRHR2 signaling is associated with anxiolytic effects, dampening anxiety and promoting stress-coping mechanisms. In the periphery, CRHR2 activity in the cardiovascular system modulates heart rate and blood pressure, while in the gastrointestinal tract it influences gut motility and appetite suppression.

Pharmacologically, CRHR2 has emerged as a compelling target for stress-related and metabolic disorders, though its therapeutic modulation is complex. Agonists of CRHR2 have been investigated for anxiety and heart failure due to their ability to promote adaptive stress recovery and improve cardiac output. Conversely, antagonists have been explored for their potential to stimulate appetite in conditions like anorexia nervosa. The development of selective CRHR2 ligands has proven challenging, but it remains a major focus of research for its unique role in counterbalancing the anxiogenic and excitatory effects of the CRHR1 pathway, offering a complementary approach to managing stress pathophysiology.