The Corticotropin-Releasing Factor (CRF) Family of Neuropeptides in Inflammation: Potential Therapeutic Applications

Abstract

Hypothalamic CRF plays a central role in the coordination of endocrine and behavioral responses to stress and it is also involved in the pathophysiology of several neuropsychiatric diseases including depression, anxiety and addiction. In the mammals, the CRF family of peptides includes CRF, urocortin (Ucn), Ucn I, and Ucn II while was enriched with new members, the urocortins. Their biological effects are mediated by the CRF1 and CRF2 receptors, which belong to the G-protein-coupled receptor super family. Multiple research groups have demonstrated during the last decade the expression of the CRF peptides and their receptors in several components of the immune system and their participation in the ad hoc regulation of inflammatory phenomena. Non-peptide CRF1 antagonists have been recently synthesized for the treatment of CNS related diseases, such as anxiety, depression and drug abuse. In the gastrointestinal tract, these compounds open new therapeutic options in the treatment of lower-GI inflammatory diseases associated to CRF, such as the chronic inflammatory bowel syndromes, irritable bowel disease and ulcerative colitis while Ucn, Ucn I, Ucn II or synthetic non-peptide CRF2 agonists may be useful in the treatment of upper-GI inflammatory diseases. In human endometrium, CRF1 antagonists may be used as abortive agents interfering with the inflammatory phenomena taking place during the implantation of the conceptus. They thus may represent a new class of nonsteroidal inhibitors of implantation. These two examples illustrate the potential therapeutic significance of the CRH in regulating inflammatory phenomena in an ad hoc approach without affecting the rest of the immune system.

The Irritable Bowel Syndrome: How Stress Can Affect the Amygdala Activity and the Brain-Gut Axis

“…Ucn 1, Ucn 2 (also known as stresscopin-related peptide), and Ucn 3 (also known as stresscopin). CRF and the Ucns exert their biological actions on target cells through activation of two 7-transmembrane-domain G protein-coupled receptors, known as CRF receptor type 1 (CRF1) and CRF receptor type 2 (CRF2) which are encoded by 2 distinct genes [for review (Gravanis and Margioris 2005)]. CRF and Ucn 1 have equal affinity for the CRF1 receptor, although Ucn 1 is 40 times more potent than CRF in binding CRF2.…”

Activation of Corticotropin-Releasing Factor Receptor 1 Selectively Inhibits CaV3.2 T-Type Calcium Channels

“…The two major receptors for CRF and UCNs, CRF receptor (CRFR)1 and CRFR2, have been identified as G protein-coupled receptors (GPCRs) that can mediate responses via activation of the protein kinase signaling pathways (Bruijnzeel and Gold, 2005;Gravanis and Margioris, 2005). CRF has a higher affinity for CRFR1 than for CRFR2, UCN shows high affinity for both CRFR1 and CRFR2, whereas UCN2 and UCN3 are selective for CRFR2 (Bale and Vale, 2004).…”

“…The inhibition of Ca V 3.2 channels via the activation of CRFR1 was due to a hyperpolarized shift in their steady-state inactivation, and it was reversible upon washout of the agonists. Given that UCN affect multiple aspects of cardiac and neuronal physiology and that Ca V 3.2 channels are widespread throughout the cardiovascular and nervous systems, the results point to a novel and functionally relevant CRFR1-Ca V 3.2 T-type calcium channel signaling pathway.The corticotropin-releasing factor (CRF) family, consisting of CRF, urocortin 1 (UCN), UCN2, and UCN3, are critical regulators of stress and inflammatory responses, and they have been variously associated with being cardioprotective and contributing toward alcohol and drug dependencies (Reul and Holsboer, 2002;Bale and Vale, 2004;Bruijnzeel and Gold, 2005;Gravanis and Margioris, 2005). The two major receptors for CRF and UCNs, CRF receptor (CRFR)1 and CRFR2, have been identified as G protein-coupled receptors (GPCRs) that can mediate responses via activation of the protein kinase signaling pathways (Bruijnzeel and Gold, 2005;Gravanis and Margioris, 2005).…”

Alanine Scanning Mutagenesis of the Second Extracellular Loop of Type 1 Corticotropin-Releasing Factor Receptor Revealed Residues Critical for Peptide Binding

“…In addition to its major role in the regulation of the hypothalamic-pituitary-adrenal axis, CRF also functions as a neurotransmitter within the central nervous system, and it is involved in the control of the gastrointestinal, behavioral, immune, and reproductive systems (Venihaki and Majzoub, 2002;Martinez et al, 2004;Gravanis and Margioris, 2005;Hillhouse and Grammatopoulos, 2006).…”