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Expression of Human Prepro-Orexin and Signaling Characteristics of Orexin Receptors in the Male Reproductive System

Biomedical Research Institute, Department of Biological Sciences, University of Warwick, Coventry, United Kingdom CV4 7AL

Address all correspondence and requests for reprints to: Dr. Harpal S. Randeva, Department of Biological Sciences, University of Warwick, Gibbet Hill Road, Coventry, United Kingdom CV4 7AL. E-mail: hrandeva{at}bio.warwick.ac.uk.

Orexin-A (OR-A) and OR-B are derived from a common 130-amino acid precursor peptide, prepro-OR, by proteolytic cleavage. Orexins orchestrate their actions by binding and activating two types of G protein-coupled receptors, OR-1 receptor (OX1R) and OR-2 receptor (OX2R). Besides playing a role in the regulation of feeding and energy homeostasis in rats, ORs appear to increase sexual arousal as well as copulatory performance in rats. Furthermore, OR-A and -B immunoreactivity has been detected in rat testis. In view of these findings we investigated the expression of OR receptors and their signaling characteristics in the human male reproductive system. Using RT-PCR analysis, we were able to demonstrate that both OX1R and OX2R are expressed in the testis, epididymis, penis, and seminal vesicle, whereas prepro-OR was expressed only in the epididymis and penis. Protein expression of both OR receptors in human testis was confirmed by Western blotting analysis, with apparent molecular masses of 50 kDa for OX1R and 40 kDa for OX2R. Immunofluorescent studies revealed staining for both OX1R and OX2R in Leydig cells, myoid cells of the seminiferous tubules, and Sertoli cells. To test the ability of ORs to activate testicular phospholipase C, we determined the effects of OR-A and OR-B on inositol trisphosphate production. When membranes from testicular biopsies were incubated with OR-A or OR-B, there was a rapid inositol trisphosphate turnover. This effect appeared to be dose dependent. These data provide a novel insight into the expression and signaling characteristics of OR receptors in the human male reproductive system and potentially further implicate these peptides, acting in an autocrine/paracrine manner, in the regulation of arousal mechanisms in humans.

This work was supported by the General Charities of City of Coventry.

E.K. and J.C. should be considered first coauthors by virtue of their equal contributions to the study.

Abbreviations: IP₃, Inositol trisphosphate; OR, orexin; OX1R, orexin-1 receptor; OX2R, orexin-2 receptor; nNOS, neuronal NO synthase; NO, nitric oxide; NOS, NO synthase; PLC, phospholipase C; PMSF, phenylmethylsulfonylfluoride; SDS, sodium dodecyl sulfate; T, testosterone; TPMC, testicular peritubular myoid cell; UCN, urocortin.

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