Testis

Dual Role of Histamine in Modulation of Leydig Cell Steroidogenesis via HRH1 and HRH2 Receptor Subtypes

Abstract
Although several reports indicate effects of histamine (HA) on female reproductive functions, little literature exists suggesting a physiological role of HA in the male gonad. In the present study, we report a dual concentration-dependent effect of HA on steroidogenesis in MA-10 murine Leydig cells and purified rat Leydig cells. While 1 nM HA can stimulate steroid production and significantly increase the response to LH/hCG in these cells, 10 µM HA exerts an inhibitory effect. We also provide confirming evidence for the existence of functional HRH1 and HRH2 receptors in both experimental models. The use of HRH1 and HRH2 selective agonists and antagonists led us to suggest HRH2 activation would be largely responsible for stimulation of steroidogenesis, while HRH1 activation is required for inhibition of steroid synthesis. Our results regarding signal transduction pathways associated with these receptors indicate the coupling of HRH2 to the adenylate cyclase system through direct interaction with a Gs protein. Moreover, we show HRH1 activation mediates increases in IP production, possibly due to coupling of this receptor to Gq protein and phospholipase C activation. The data compiled in this report clearly indicate HA can modulate Leydig cell steroidogenesis in the testis and suggest a possible new physiological site of action for HA. Given the fact that many drugs binding to HRH1 and/or HRH2 are widely prescribed for the treatment of diverse HA-related pathologies, it seems necessary to increase the knowledge regarding histaminergic regulation of testicular functions, to avoid possible unexpected side-effects of such substances in the testis.

Key words: Testis • Cyclic adenosine monophosphate • Leydig cells • Signal transduction • Testosterone

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