Emerging Role of Alternative Splicing of CRF1 Receptor in CRF Signaling
Overview
Affiliations
Alternative splicing of mRNA is one of the most important mechanisms responsible for an increase of the genomic capacity. Thus the majority of human proteins including G protein-coupled receptors (GPCRs) possess several isoforms as a result of mRNA splicing. The corticotropin-releasing factor (CRF) and its receptors are the most proximal elements of hypothalamic-pituitary-adrenal axis (HPA) - the central machinery of stress response. Moreover, expression of CRF and regulated activity of CRF receptor type 1 (CRF1) can also play an important role in regulation of local stress response in peripheral tissues including skin, gastrointestinal tract or reproductive system. In humans, expression of at least eight variants of CRF1 mRNA (alpha, beta, c, d, e, f, g and h) was detected and alternative splicing was found to be regulated by diverse physiological and pathological factors including: growth conditions, onset of labor, during pregnancy or exposure to ultraviolet irradiation. The pattern of expression of CRF1 isoforms is cell type specific and recently has been linked to observed differences in responsiveness to CRF stimulation. In the proposed model of regulation of CRF-signaling, isoform CRF1alpha plays a central role. Other isoforms modulate its activity by oligomerization, leading to alteration in receptor trafficking, localization and function. Co-expression of CRF1 isoforms modulates sensitivity of cells to the ligands and influences downstream coupling to G-proteins. The other possible regulatory mechanisms include fast mRNA and/or protein turnover or decoy receptor function of CRF1 isoforms. Taken together, alternative splicing of CRF1 can represent another level of regulation of CRF-mediated stress responses at the central and peripheral levels. Chronic stress or malfunction of the HPA-axis have been linked to numerous human pathologies, suggesting that alternative splicing of CRF1 receptor could represent a promising target for drugs development.
Barretto-de-Souza L, Benini R, Reis-Silva L, Busnardo C, Crestani C Pflugers Arch. 2024; 476(3):351-364.
PMID: 38228895 DOI: 10.1007/s00424-024-02904-5.
Neuroendocrine signaling in the skin with a special focus on the epidermal neuropeptides.
Slominski A, Slominski R, Raman C, Chen J, Athar M, Elmets C Am J Physiol Cell Physiol. 2022; 323(6):C1757-C1776.
PMID: 36317800 PMC: 9744652. DOI: 10.1152/ajpcell.00147.2022.
Modulation of dermal equivalent of hypothalamus-pituitary-adrenal axis in mastocytosis.
Antoniewicz J, Nedoszytko B, Lange M, Wierzbicka J, Gorska-Ponikowska M, Niedoszytko M Postepy Dermatol Alergol. 2021; 38(3):461-472.
PMID: 34377129 PMC: 8330854. DOI: 10.5114/ada.2021.107933.
Samotij D, Nedoszytko B, Bartosinska J, Batycka-Baran A, Czajkowski R, Dobrucki I Postepy Dermatol Alergol. 2020; 37(2):135-153.
PMID: 32489346 PMC: 7262814. DOI: 10.5114/ada.2020.94832.
Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders.
Slominski R, Tuckey R, Manna P, Jetten A, Postlethwaite A, Raman C Genes Immun. 2020; 21(3):150-168.
PMID: 32203088 PMC: 7276297. DOI: 10.1038/s41435-020-0096-6.