The study shows that the hormone ghrelin can lower the activity of a specific calcium channel (T-type) in mouse sperm cells, and this effect works through the growth hormone secretagogue receptor (GHS‑R1a) using a novel protein‑kinase‑C pathway. Blocking this receptor with a GHRP‑6‑derived antagonist stops the effect, suggesting the pathway could be part of how ghrelin influences male fertility.

Ghrelin, a newly isolated brain-gut peptide, has been found to play important roles in the male reproduction. However, to date, the detailed mechanisms still remain unknown. In this study, we identified a novel functional role of ghrelin in modulating T-type Ca(2+) channel currents (T-currents) in mouse spermatogenic cells. We found that ghrelin inhibited T-currents in a dose-dependent manner. Ghrelin at 0.1 μM reversibly inhibited T-currents by ∼31.7%. This inhibitory effect was blocked by D-Lys3-GHRP-6, a selective growth hormone secretagogue receptor 1a (GHS-R1a) antagonist. Intracellular infusion of GDP-b-S or pretreatment of the cells with pertussis toxin (PTX) completely blocked the inhibitory effects of ghrelin. Furthermore, ghrelin responses were abolished by the phospholipase C inhibitor U73122, but not the inactive analogue U73343. The classical and novel protein kinase C antagonist chelerythrine chlorid or GF109203X abolished ghrelin responses, whereas Ro31-8820, a classical PKC antagonist or PKI 6-22, a PKA antagonist, elicited no such effects. Taken together, these results suggest that ghrelin acting through GSH-R1a inhibits T-currents via a PTX-sensitive novel PKC pathway in mouse spermatogenic cells, which could contribute to its male reproductive functions such as acrosome reactions.