To maintain homeostatic equilibrium, living organisms have evolved complex adaptation systems
that control an array of behavioural, autonomic, neuroendocrine and immune responses. One of the
important switches of this system is the hypothalamic hormone corticotropin-releasing hormone (CRH),
which together with a family of related peptides (urocortins, UCNs) orchestrate stress-coping responses
that reinstate homeostasis. Persistent disturbances in the homeostatic equilibrium either due to inadequate
or persistently uncontrolled responses have been associated with pathogenic mechanisms of disease. CRH
and UCNs exert their actions by activating two receptors of the Class B1 GPCRs, CRH-R1 and CRH-R2.
Their signalling versatility allows activation of multiple and diverse signalling pathways characterized by
‘cell-specific agonist-dependent signalling’ responses. Alternative mRNA splicing, interactions with intracellular
protein partners and mechanisms that allow selective regulation of signalling potency and termination,
provide additional levels of regulation to fine-tune cellular responses. Although understanding of
CRH-R signalling is still incomplete, recent important advances in decoding CRH-R structure and signalling
properties uncovered key important functions and roles in physiology and pathobiology.
Keywords: Stress, CRH, urocortins, GPCRs, cAMP, ERK1/2, neuroendocrine, immune responses, mRNA splicing, intracellular
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