CRHR1

Official Full Name

corticotropin releasing hormone receptor 1

Organism

Homo sapiens

GeneID

1394

Background

This gene encodes a G-protein coupled receptor that binds neuropeptides of the corticotropin releasing hormone family that are major regulators of the hypothalamic-pituitary-adrenal pathway. The encoded protein is essential for the activation of signal transduction pathways that regulate diverse physiological processes including stress, reproduction, immune response and obesity. Alternative splicing results in multiple transcript variants. Naturally-occurring readthrough transcription between this gene and upstream GeneID:147081 results in transcripts that encode isoforms that share similarity with the products of this gene. [provided by RefSeq, Aug 2016]

Synonyms

CRF1; CRHR; CRF-R; CRFR1; CRF-R1; CRFR-1; CRH-R1; CRHR1L; CRF-R-1; CRH-R-1;

Bio Chemical Class

GPCR secretin

Protein Sequence

MGGHPQLRLVKALLLLGLNPVSASLQDQHCESLSLASNISGLQCNASVDLIGTCWPRSPAGQLVVRPCPAFFYGVRYNTTNNGYRECLANGSWAARVNYSECQEILNEEKKSKVHYHVAVIINYLGHCISLVALLVAFVLFLRLRPGCTHWGDQADGALEVGAPWSGAPFQVRRSIRCLRNIIHWNLISAFILRNATWFVVQLTMSPEVHQSNVGWCRLVTAAYNYFHVTNFFWMFGEGCYLHTAIVLTYSTDRLRKWMFICIGWGVPFPIIVAWAIGKLYYDNEKCWFGKRPGVYTDYIYQGPMILVLLINFIFLFNIVRILMTKLRASTTSETIQYRKAVKATLVLLPLLGITYMLFFVNPGEDEVSRVVFIYFNSFLESFQGFFVSVFYCFLNSEVRSAIRKRWHRWQDKHSIRARVARAMSIPTSPTRVSFHSIKQSTAV

Open

Disease

Adrenogenital disorder, Anxiety disorder, Depression, Irritable bowel syndrome, Mood disorder, Staphylococcal/streptococcal disease, Substance abuse

Approved Drug

1 +

Clinical Trial Drug

7 +

Discontinued Drug

5 +

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Detailed Information

Corticotropin-Releasing Hormone Receptor 1 (CRHR1) is a pivotal member of the Class B/Secretin-like G protein-coupled receptor family, playing a central role in stress response regulation. The CRHR1 gene can produce multiple splice variants (α, β, c-n), with CRHR1α being the primary biologically active form. Structurally, CRHR1 features a typical extracellular N-terminal domain (ECD), comprising a "sushi domain" constructed from a three-layer α-β-βα fold and disulfide bonds. Recent cryo-electron microscopy has elucidated the fine structure of CRHR1 complexed with ligands and G proteins, revealing multiple cholesterol-binding sites, indicating the significant impact of the lipid environment on its signal transduction. The binding of CRHR1 to ligands follows a "two-domain model": the ligand's carboxyl terminus initially binds to the N-terminal of the ECD, followed by the ligand's amino terminus associating with the transmembrane domain, thereby stabilizing the receptor's active conformation and altering its interaction with G proteins. Regarding ligand selectivity, CRH and UCN1 have high affinity for CRHR1, while UCN2 and UCN3 exhibit lower affinity.

Expression Distribution in the Central Nervous System and Physiological Functions

CRHR1 is extensively expressed throughout the brain, serving as the predominant receptor subtype in the CRH system. Its expression is particularly rich in the limbic system and hippocampus. Research indicates that CRHR1 plays a crucial role in stress response, anxiety behavior, memory formation, and learning. In the hippocampus, CRHR1 activation enhances synaptic plasticity and long-term potentiation (LTP), essential cellular mechanisms for memory formation and learning. This effect is beneficial for adaptive response formation under acute stress conditions. However, chronic stress or persistent strong stimulus activation of CRHR1 can lead to neuronal structural changes, impairing hippocampal function. Recent studies have also revealed that CRHR1 is instrumental in neurogenesis within the hippocampal dentate gyrus, a function independent of its stress regulatory role. In various neurotransmitter systems, CRHR1 may exert antagonistic regulatory effects to achieve adaptive response balance under stress conditions.

Intracellular Signal Transduction Network

Upon activation, CRHR1 can trigger complex intracellular signaling networks. Traditionally, CRHR1 is thought to primarily activate adenylyl cyclase (AC) via Gαs to produce cAMP, subsequently activating protein kinase A (PKA). However, recent studies reveal that CRHR1's signal transduction is far more complex than previously recognized. In different cellular environments, CRHR1 can couple with various G protein subtypes (including Gs, Go, Gq/11, Gz, and Gi1/2), regulating different downstream effectors. Among these, the ERK1/2 MAPK pathway is a critical component of CRHR1 signaling, playing key roles in neural plasticity, learning and memory, and stress response. CRHR1-mediated ERK1/2 activation exhibits a biphasic nature: an acute phase appearing 3-6 minutes post-stimulation, and a sustained phase lasting over 60 minutes. This biphasic activation pattern involves at least two different mechanisms: one dependent on G proteins, and the other on β-arrestin2 and receptor internalization.

Figure 1 illustrates CRHR1 signaling in the hippocampus. Upon CRH stimulation, CRHR1 triggers rapid calcium influx and elevates cAMP levels through tmACs and sAC, engaging PKA and EPAC to activate the B-Raf/MEK/ERK pathway (early phase). Figure 1. CRHR1 signaling pathways in the hippocampus. (Dos Santos Claro PA, et al., 2023)

Receptor Internalization and Sustained Signal Regulation

Similar to other G protein-coupled receptors, activated CRHR1 undergoes internalization. However, internalization is not merely a mechanism to terminate signaling. Recent studies indicate that the endosomal network is a vital regulatory platform for intracellular communication, capable of assembling specific signaling complexes and modulating the spatiotemporal characteristics of signaling. Internalized CRHR1 can continue signaling within the endosomal network, eliciting biological effects distinct from those on the cell surface. Real-time monitoring techniques have uncovered that CRHR1-induced cAMP responses exhibit different dynamics in various cellular environments: transient responses in pituitary cells versus sustained responses in cortical and hippocampal neurons. In-depth research reveals that these differential responses originate from various cAMP sources: both transmembrane adenylyl cyclase (tmAC) and soluble adenylyl cyclase (sAC) are involved, but they have different intracellular distributions and regulatory characteristics.

Pathophysiological Significance and Therapeutic Target Value

CRHR1 plays a significant role in the pathogenesis of various neuropsychiatric disorders. Clinical research shows that the stress-induced effects of CRH are mainly mediated through CRHR1. Variations in signaling molecules (such as β-arrestins and GRKs) due to genetic or environmental factors can lead to CRHR1 dysfunction, which is related to gender differences in certain diseases. For instance, the higher susceptibility to depression in females might be associated with reduced CRHR1 internalization. In Alzheimer's disease, CRH-overexpressing mice exhibit gender-dependent signaling biases: enhanced β-arrestin2 signaling in males, and increased Gs-dependent responses in females. These findings not only deepen our understanding of CRHR1 signal transduction but also provide important clues for developing novel therapeutic strategies. Currently, drugs targeting G proteins have shown therapeutic effects in preclinical models, and further understanding of CRHR1's signal regulation mechanisms will aid in identifying more potential therapeutic targets.

References:

Dos Santos Claro PA, Silbermins M, et al. CRHR1 endocytosis: Spatiotemporal regulation of receptor signaling. Prog Mol Biol Transl Sci. 2023;196:229-260.
Chrousos GP, Zoumakis E. Milestones in CRH Research. Curr Mol Pharmacol. 2017;10(4):259-263.
Tache Y, Larauche M, et al. Brain and Gut CRF Signaling: Biological Actions and Role in the Gastrointestinal Tract. Curr Mol Pharmacol. 2018;11(1):51-71.

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