Corticotropin releasing hormone and the skin

Abstract

Cotricotropin-releasing hormone (CRH) and related peptides are produced in skin that is dependent on species and anatomical location. Local peptide production is regulated by ultraviolet radiation (UVR), glucocorticoids and phase of the hair cycle. The skin also expresses the corresponding receptors (CRH-R1 and CRH-R2), with CRH-R1 being the major receptor in humans. CRH-R1 is expressed in epidermal and dermal compartments, and CRH-R2 predominantly in dermal structures. The gene coding for CRH-R1 generates multiple isoforms through a process modulated by UVR, cyclic adenosine monophosphate (cAMP) and phorbol 12-myristate 13-acetate. The phenotypic effects of CRH in human skin cells are largely mediated by CRH-R1alpha through increases in concentrations of cAMP, inositol triphosphate (IP 3 ), or Ca 2+ with subsequent activation of protein kinases A (PKA) and C (PKC) dependent pathways. CRH also modulates the activity of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kappaB), activator protein 1 (AP-1) and cAMP responsive element binding protein (CREB). The cellular functions affected by CRH depend on cell type and nutritional status and include modulation of differentiation program(s), proliferation, viability and immune activity. The accumulated evidence indicates that cutaneous CRH is also a component of a local structure organized similarly to the hypothalamo-pituitary-adrenal axis. KeywordsHuman Skin; Hormone; Corticotropin; CRH; CRH-R1; CRH-R2; Urocortin; Review INTRODUCTIONCRH is the central trigger of HPA axis, and together with related peptides urocortin I-III also regulate behavioral, autonomic, endocrine, reproductive, cardiovascular, gastro-intestinal, metabolic and immune systemic functions (1-11). Other actions include local immunomodulatory (predominantly proinflammatory) effects (12)(13)(14), differing from a central immunosuppressive activity (through the HPA axis) (3). Of note, locally produced CRH can directly regulate steroid hormone production by adrenals and gonads (1,2). Furthermore, CRH in the immune cells can induce production and release of proopiomelanocortin (POMC) derived adrenocorticotropin (ACTH) and beta-endorphin peptides. NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2007 April 2. Published in final edited form as:Front Biosci. ; 11: 2230-2248. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn vertebrates these peptides interact with membrane-bound CRH-R1 and CRH-R2 (1,2). Both receptor types belong to the group II subfamily of G protein-coupled receptors (GPCRs). CRH-R1 binds CRH and urocortin I with high affinity; it does not bind urocortin II (strescopin related protein). CRH-R2 shows preferential affinity for urocortin II, although it also binds CRH, however, with lower affinity than CRH-R1. Signal transduction through CRH-Rs is coupled to the activation of adenylate cyclase (AC), phospholipase C (PLC) and calcium channels (1, 2,5,6). ALTERNATIVELY SPLICED CRH-RS ISOFORMS: AN OVER...

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

“…Melanocytes and melanoma cells express G protein-coupled CRH-R1 responding to CRH and urocortin peptides (exogenous or produced locally) through activation of cAMP, IP3, and Camediated pathways to modify the melanocyte phenotype [30,58,59]. In both normal and immortalized melanocytes, CRH inhibited cell proliferation in serum-containing medium, while inhibiting early and late apoptosis in serum free media [58].…”

“…Concerning melanoma cells, the effect was heterogenous depending on cell line [58,60]. The variability in CHR action on melanoma cells could be explained by co-expression of alternatively spliced CRH-R1 isoforms on the same cells that would modify the action of the CRH-R1α isoform [30,59]. Of significance, an antimelanoma effect for selective CRH-R1 agonists has already been observed in experimental models of melanoma in vivo [60].…”

Molecular cloning and initial characterization of African green monkey (Cercopithecus aethiops) corticotropin releasing factor receptor type 1 (CRF1) from COS-7 cells

“…We therefore used COS-7 cells to study the properties of alternatively spliced CRF1 isoforms recently cloned in skin cells Pisarchik, Slominski, 2002;Pisarchik, Slominski, 2004). Unexpectedly, we found functionally active endogenous CRF1 in the COS-7 cells, which had properties similar to those described in human cells expressing the CRF1 (Slominski et al, 2006b). We also cloned the coding region of the African green monkey CRF1 gene and sequenced its alternatively spliced isoforms.…”

“…Moreover, the same peptides are also expressed in peripheral organs where they act locally to regulate homeostasis in situ (Chrousos, Gold, 1992;Perrin, Vale, 1999;Linton et al, 2001;Slominski et al, 2001;Hillhouse, Grammatopoulos, 2006;Slominski et al, 2006b). These diverse phenotypic effects are mediated through interaction with G protein coupled membrane bound CRF receptors (CRF1 and CRF2) (Perrin, Vale, 1999;Hillhouse, Grammatopoulos, 2006).…”

“…These diverse phenotypic effects are mediated through interaction with G protein coupled membrane bound CRF receptors (CRF1 and CRF2) (Perrin, Vale, 1999;Hillhouse, Grammatopoulos, 2006). The gene for mammalian CRF1 has been cloned in humans, rat, mouse, hamster, sheep, bovine, tree shrew, chicken and rhesus monkey (Chen et al, 1993;Vita et al, 1993;Yu et al, 1996;Myers et al, 1998;Palchaudhuri et al, 1998;Perrin, Vale, 1999;Pisarchik, Slominski, 2002;Oshida et al, 2004;Hillhouse, Grammatopoulos, 2006); and more specifically, the genes for human and rodent CRF1 contain 14 and 13 exons, respectively (Tsai-Morris et al, 1996;Sakai et al, 1998;Parham et al, 2004), and produce several alternatively spliced isoforms (reviewed in (Hillhouse, Grammatopoulos, 2006;Slominski et al, 2006b)). …”