Two olfactory receptors—OR2A4/7 andOR51B5—differentially affect epidermal proliferation and differentiation

Abstract

Olfactory receptors (ORs), which belong to the G-protein coupled receptor family, are expressed in various human tissues, including skin. Cells in non-olfactory tissues tend to express more than one individual OR gene, but function and interaction of two or more ORs in the same cell type has only been marginally analysed. Here, we revealed OR2A4/7 and OR51B5 as two new ORs in human skin cells and identified cyclohexyl salicylate and isononyl alcohol as agonists of these receptors. In cultured human keratinocytes, both odorants induce strong Ca signals that are mediated by OR2A4/7 and OR51B5, as demonstrated by the receptor knockdown experiments. Activation of corresponding receptors induces a cAMP-dependent pathway. Localization studies and functional characterization of both receptors revealed several differences. OR2A4/7 is expressed in suprabasal keratinocytes and basal melanocytes of the epidermis and influences cytokinesis, cell proliferation, phosphorylation of AKT and Chk-2 and secretion of IL-1. In contrast, OR51B5 is exclusively expressed in suprabasal keratinocytes, supports cell migration and regeneration of keratinocyte monolayers, influences Hsp27, AMPK1 and p38MAPK phosphorylation and interestingly, IL-6 secretion. These findings underline that different ORs perform diverse functions in cutaneous cells, and thus offering an approach for the modulated treatment of skin diseases and wound repair.

Deep Sequencing of the Human Retinae Reveals the Expression of Odorant Receptors

“…Based on this observation, we assume that the OR expression in the human retina is sufficiently high to be an indicator of functionality. The fact that ORs are also weakly to moderate expressed in term of FPKM value in the olfactory epithelium, where they perform their main task in mediating olfaction, and in other cell types such as keratinocytes, where they are involved in growth processes, support this assumption (Olender et al, 2016; Tsai et al, 2016). …”

“…These findings have served as a basis for functional studies that demonstrate the potential of the ORs as drug targets (Neuhaus et al, 2009; Busse et al, 2014; Maßberg et al, 2015; Manteniotis et al, 2016a,b; Tsai et al, 2016). In this study, for the first time, we describe the expression of the OR mRNAs and the localization of the OR proteins in the mature human retina.…”

“…Thus, OR mediated signaling pathways may interact with the dopaminergic system in the retina, which regulates the circadian rhythms in the eye as a counterpart to the melatonin system. Dopamine receptors are also involved in cell survival and growth processes in the eye (Witkovsky, 2004) such as ectopically expressed ORs in prostate and keratinocytes (Massberg et al, 2016; Tsai et al, 2016). Interestingly, the expression level of dopamine receptors already described in retina such as D1 receptor ( DRD1 : mFPKM 9) is comparable to that of ORs (Supplementary Figure S11).…”

“…OR2AT4 is another example of the therapeutic potential of ORs in human skin because its activation promotes wound healing processes in human keratinocytes (Busse et al, 2014). They are also of major importance for the regulation of apoptosis, cytokinesis, hormone secretion and differentiation (Braun et al, 2007; Zhang et al, 2012; Maßberg et al, 2015; Gelis et al, 2016; Manteniotis et al, 2016a,b; Massberg et al, 2016; Tsai et al, 2016). However, the expression and localization of ORs in different areas of the brain, the spinal cord, the trigeminal (TG) and dorsal root ganglia (DRG) were recently described (Otaki et al, 2004; Garcia-Esparcia et al, 2013; Flegel et al, 2015; Goncalves et al, 2016).…”

Ectopic expression of olfactory receptors and associated G‐protein subunits in the head integument of the amphihaline migratory fish hilsa Tenualosa ilisha

“…In an odorant receptor knockdown experiment, Tsai et al . () showed that cyclohexyl salicylate and isononyl alcohol stimulated strong Ca 2+ signals in cultured human keratinocytes mediated by odorant receptor OR2A4/7 (and OR51B5). In T. ilisha , the keratinocytes from the SP also showed intense localization with OR2A4 and Gαs‐olf.…”