Functional Characterization of Transient Receptor Potential (TRP) Channel C5 in Female Murine Gonadotropes.

Abstract

Gonadotrope cells in the anterior pituitary gland secrete gonadotropins regulating gonadal function in mammals. Recent results have implicated transient receptor potential (TRP) cation channels in pituitary physiology; however, if and how TRP channels contribute to gonadotrope function is not known. Here, we report that 14 out of 28 TRP channels encoded in the mouse genome are expressed in murine gonadotropes with highest expression levels found for canonical TRP (TRPC) channel 5 in juvenile females. We show that TRP channel expression in these cells exhibits considerable plasticity and that it depends on the sex and the developmental and hormonal status of the animal. We then combine different genetic strategies including genetic confocal Ca2+ imaging in whole-mount pituitary gland preparations to characterize TRPC5 channel function in gonadotropes from juvenile females. We show that the TRPC5 agonist Englerin A activates a cytosolic Ca2+ signal and a whole-cell current in these cells, which is absent in TRPC5-deficient mice, and demonstrate that TRPC5 forms functional heteromultimers with TRPC1 in gonadotropes. We further show that the Englerin A-activated TRPC5-dependent Ca2+ signal is mediated by Ca2+ influx both via TRPC5 and via l-type voltage-gated Ca2+ channels, activated by the depolarization through TRPC5-mediated cation influx. Finally, we demonstrate that the gonadotropin-releasing hormone (GnRH)-mediated net depolarization is significantly reduced in gonadotropes isolated from TRPC5-deficient mice. In conclusion, our data suggest that TRPC5 contributes to depolarization of the plasma membrane in gonadotropes upon GnRH stimulation and increases the intracellular Ca2+ concentration via its own Ca2+ permeability and via the activation of voltage-gated Ca2+ channels.