Corticotropin-Releasing Factor (CRF) and Analogs

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Introduction

Corticotropin-Releasing Factor (CRF) and analogs are neuroendocrine peptides that are mainly synthesized and released by neurons in the hypothalamic paraventricular nucleus and are closely related to stress response. CRF was extracted from the sheep hypothalamus in 1981. Their family members mainly include CRF and CRF-related peptides Ucn1, Ucn2, Ucn3, and so on. CRF and its related peptides and receptors (corticotropin-releasing factor receptors, CRFRs) are present in the central nervous system as well as in a variety of peripheral tissues. Members of the CRF family, by binding to CRFR, regulate the hypothalamic-pituitary-adrenal (HPA) axis function of the body under stress. They play an important role in coordinating stress-related endocrine, autonomic, immune, and behavioral responses. Their functions mainly involve the central nervous system, cardiovascular system, gastrointestinal tract, muscles and skin.

Mechanism of action

CRF and its related peptides mainly exert biological effects by activating CRFRs, and different CRF family members have different specific sites for binding to CRFR. When the two are combined, the intracellular adenylate cyclase or phosphatidylinositol-specific phospholipase C is activated by the CRFR-conjugated G protein. This stimulates the production of cyclic adenosine monophosphate (cAMP) and the hydrolysis of phosphatidylinositol diphosphate (PIP2) to diacylglycerol (DG) and inositol triphosphate (IP3). In turn, protein kinase A (PKA) or protein kinase C (PKC) is activated to cause functional protein expression and exert biological effects. CRFR is widely expressed in the human central nervous system and peripheral tissues. Different subtypes of receptors have different tissue distributions, activate different signaling pathways, and produce various biological effects.

Application of Corticotropin-Releasing Factor (CRF) and Analogs

During the intestinal inflammatory response, the interaction between the HPA axis and the immune system is balanced. CRF can produce glucocorticoids through the HPA shaft, indirectly exert anti-inflammatory effects, and can also act on immune cells to directly exert pro-inflammatory effects. CRFR-targeted drugs may become a new approach to clinical treatment of inflammatory bowel disease (IBD). Synthetic CRFR1 antagonists have an anti-inflammatory effect in animal models, supporting CRFR1 as a targeted therapeutic site for inflammatory bowel disease (IBD).

Reference

1. Kiank, C., Taché, Y., Larauche, M.(2010) Stress-related modulation of inflammation in experimental models of bowel disease and post-infectious irritable bowel syndrome: role of corticotropin-releasing factor receptors. Brain Behav Immun, 24(1): 41-48