System-Wide Expression of Olfactory Receptors

Testis
In 1992, ectopic expression of OR-like proteins in dog testis was reported after the OR multigene family was originally isolated from rat olfactory epithelium [7]. Subsequently, many experiments were performed to trace the presence of ORs in animal testicular tissues for the investigation of OR function in sperm-oocyte chemotaxis, where it was thought that ORs should have chemotactic roles during fertilization. Moreover, ORs are also thought to be involved in chemotaxis [74] and cytokinesis [75], and dozens of ORs were found to be expressed in the testis of mammals using deep sequencing [32]. Several tens of ORs were expressed in testicular tissues of mammals, and their roles in sperm-oocyte chemotaxis were investigated. Very recently, Milardi et al. [33] suggested that the presence of ORs, such as OR4S1, OR4C13, and OR1I1, on mature cells might be related to acrosome activity and sperm motility after a proteomic analysis. Itakura et al. [34] also identified Gαolf and several kinds of ORs from rat placenta using RT-PCR, western blotting, and immunochemical methods. They suggested that ORs may recognize some small molecules in the placenta as environmental signals and mediate the growth of the fetus.

Tongue and gastrointestinal tract
Since three transcripts of OR were identified in rat taste organs and reproductive tissues using an RT-PCR strategy [36], ORs, as well as TASRs, were isolated in the tongue of human [37, 38] and mouse [39]. In mouse, northern analysis revealed that the homolog of PSGR (Olfr78), an OR, was predominantly expressed in colon [15]. In the case of human, the expression of four ORs, including OR73 (OR5D18), hOR17-7/11 (OR1A1), OR1G1, and hOR17-210 (OR1E3), in the enterochromaffin cells of human gut was confirmed [40]. Amperometric detection using Ca2＋ imaging and immunostaining studies revealed that the ligands of those ORs consequently caused serotonin release. Another human OR, OR51E1, was identified from enterochromaffin cells in the jejunum and ileum of neuroendocrine carcinomas [41]. In 2015, the porcine homolog of OR51E1 was also found to be expressed along the gastrointestinal (GI) tract of pigs and modulated by intestinal microbiota [42]. Recently, human ORs (OR1A1, OR1G1, and OR51E1) and the mouse homolog of OR1A1 (Olfr43) were found to participate in glucose homeostasis during meal ingestion by inducing the secretion of gut peptides [43].
According to recent reports, ORs are expressed in non-olfactory tissues, including brain, heart, testis, tongue, GI tract, pancreas [46], spleen [15], liver [23], kidney [52], lung [53], skin [56], muscle [58], and diaphragm [30], and even cancerous tissues, such as prostate [64] and lung cancer cells [54] (Table 1).
In human primary keratinocytes, OR2AT4 is expressed and induces wound-healing processes by increasing cell proliferation and migration and regeneration of keratinocyte monolayers [55]. In this mechanism, the activation of OR2AT4 induces the phosphorylation of extracellular signal-regulated kinases (Erk1/2) and p38 mitogen-activated protein kinase (MAPK) by a cAMP-dependent pathway. This type of investigation should be applied in various fields of OR research. Another human OR, OR51E2, was detected in human epidermal melanocytes at the transcript and protein level, and its stimulation with its cognate ligand, β-ionone, significantly slows melanocyte proliferation [56]. Additional results also demonstrated that OR51E2 activation elevates cytosolic Ca2＋ and cAMP using RNA silencing and receptor antagonists. These findings suggest that OR signaling can influence melanocyte homeostasis. We surmise that ORs play a pivotal role in maintaining organismal homeostasis according to results above.