CRF1 Receptor Splicing in Epidermal Keratinocytes: Potential Biological Role and Environmental Regulations

Corticotropin releasing factor receptor type I (CRFI), a coordinator of the body responses to stress, is also expressed in human skin, where it undergoes alternative splicing. Since the epidermis is continuously exposed to the environmental stress, human keratinocytes were chosen to study the biological role of CRFI alternative splicing. The expression pattern of CRFI isoforms depended on cell density, presence or absence of serum, and exposure to ultraviolet irradiation (UVR). Only two isoforms alpha and c were predominantly localized to the cell membrane, with only CRFI alpha being efficient in stimulating cAMP responding element (CRE). CRFId, f and g had intracellular localization, showing no or very low (g) activation of CRE. The co-expression of CRFI alpha with d, f or g resulted in intracellular retention of both isoforms suggesting dimerization confirmed by detection of high molecular weight complexes. The soluble isoforms e and h were diffusely distributed in the cytoplasm or localized to the ER, respectively, and additionally found in culture medium. These findings suggest that alternatively spliced CRFI isoforms can interact and modify CRFI alpha subcellular localization, thus affecting its activity. We suggest that alternative splicing of CRFI may play an important role in the regulation. of skin cell phenotype with potential implications in pathology.