CRH family
Hypothalamic Hormones

Author: Gianpiero Pescarmona
Date: 09/03/2018

Description

Corticotropin-releasing hormone (CRH) is a key player of basal and stress-activated responses in the hypothalamic-pituitary-adrenal axis (HPA) and in extrahypothalamic circuits, where it functions as a neuromodulator to orchestrate humoral and behavioral adaptive responses to stress. This review describes molecular components and cellular mechanisms involved in CRH signaling downstream of its G protein-coupled receptors (GPCRs) CRHR1 and CRHR2 and summarizes recent findings that challenge the classical view of GPCR signaling and impact on our understanding of CRHRs function. Special emphasis is placed on recent studies of CRH signaling that revealed new mechanistic aspects of cAMP generation and ERK1/2 activation in physiologically relevant contexts of the neurohormone action. In addition, we present an overview of the pathophysiological role of the CRH system, which highlights the need for a precise definition of CRHRs signaling at molecular level to identify novel targets for pharmacological intervention in neuroendocrine tissues and specific brain areas involved in CRH-related disorders.

The main molecular components of the CRH system (A) Corticotropin-releasing hormone (CRH) is a 41-amino acid neuropeptide generated by proteolytic cleavage from a 194-amino acid precursor, followed by the amidation of the carboxyl terminus. (B) Amino acid sequence alignment of mammalian CRH family peptides that includes urocortins 1–3 (UCN1, UCN2, UCN3) showing regions of high amino acid conservation in boxes.

CRH/CRHR1 action at physiological and molecular levels (A) The HPA axis: CRH and AVP secreted from the hypothalamic PVN activate the release of ACTH from pituitary corticotrophs which, in turn, drives the synthesis and release of corticosteroids from the adrenal cortex. Corticosteroids exert a negative feedback on the hypothalamus and pituitary suppressing hormone secretion. CRH expression in extrahypothalamic circuits acts as a neuromodulator orchestrating a complex humoral and behavioral response to stress.

A new mechanism of CRH-activated CRHR1 signaling. In the classical model, CRHR1 activation by CRH is followed by a rise in cAMP mediated by G protein–dependent tmACs. Binding of β-arrestin2 to agonist-activated CRHR1 triggers receptor internalization leading to termination of agonist-activated G protein-mediated signaling. In the emerging model discussed in this work, an atypical pool of cyclic AMP is generated by soluble adenylyl cyclase (sAC) in response to CRHR1 activation in addition to cAMP generated by tmACs. In hippocampal neuronal cells cAMP was found to activate specific signaling pathways that are dependent on the source (tmACs or sAC) and cellular location (cell surface or endosomes) of the cAMP generation. In particular, sAC was critical for endosome-generated cAMP in response to CRH.

Endocrinology and the brain: corticotropin-releasing hormone signaling. 2017

CRH has no Trp

CRH inflammation

CRF

Hormone regulating the release of corticotropin from pituitary gland (By similarity). Induces NLRP6 in intestinal epithelial cells, hence may influence gut microbiota profile (By similarity).

UCN1

Acts in vitro to stimulate the secretion of adrenocorticotropic hormone (ACTH) (PubMed:8612563). Binds with high affinity to CRF receptor types 1, 2-alpha, and 2-beta (PubMed:8612563). Plays a role in the establishment of normal hearing thresholds (By similarity). Reduces food intake and regulates ghrelin levels in gastric body and plasma (By similarity)

UCN2

Suppresses food intake, delays gastric emptying and decreases heat-induced edema. Might represent an endogenous ligand for maintaining homeostasis after stress.

UCN3

Suppresses food intake, delays gastric emptying and decreases heat-induced edema. Might represent an endogenous ligand for maintaining homeostasis after stress.

CRF Receptors

CRFR1

G-protein coupled receptor for CRH (corticotropin-releasing factor) and UCN (urocortin). Has high affinity for CRH and UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. Inhibits the activity of the calcium channel CACNA1H. Required for normal embryonic development of the adrenal gland and for normal hormonal responses to stress. Plays a role in the response to anxiogenic stimuli

CRFR2

G-protein coupled receptor for CRH (corticotropin-releasing factor), UCN (urocortin), UCN2 and UCN3. Has high affinity for UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels.

Apparently on the basis of Glu/Gln ratio CRFR1 is some millions years older than CRFR2

CRFR2 acts solely via cAMP increase that requires a high O2 level
CRFR1 original activity was to inhibit the activity of the calcium channel CACNA1H protecting the cell from excessive stimulation (effect similar to cGMP); later the G-protein activation was coupled to soluble adenylate cyclase.

Attachments
fileuserdate
CRF_CRFR_ch1.gifgp09/03/2018
CRF_CRFR_ch2.gifgp09/03/2018
CRF_UCN1-3_ch1.gifgp09/03/2018
CRF_UCN1-3_ch2.gifgp09/03/2018
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