Identification of an ovarian voltage-activated Na+-channel type: Hints to involvement in luteolysis

An endocrine type of voltage-activated sodium channel (eNaCh) was identifie d in the human ovary and human luteinized granulosa cells (GC). Whole-cell patch-clamp studies showed that the eNaCh in GC is functional and tetrodoto xin (TTX) sensitive. The luteotrophic hormone human CG (hCG) was found to d ecrease the peak amplitude of the sodium current within seconds. Treatment with hCG for 24-48 h suppressed not only eNaCh mRNA levels, but also mean N a+ peak currents and resting membrane potentials. An unexpected role for eN aChs in regulating cell morphology end function was indicated after pharmac ological modulation of presumed eNaCh steady-state activity in GC cultures for 24-48 h using mt (NaCh blocker) and veratridine (NaCh activator). mt pr eserved a highly differentiated cellular phenotype. Veratridine not only in creased the number of secondary lysosomes but also led to a significantly r educed progesterone production. Importantly, endocrine cells of the nonhuma n primate corpus luteum (CL), which represent in vivo counterparts of lutei nized GC, also contain eNaCh mRNA. Although the mechanism of channel activi ty under physiological conditions is not clear, it may include persistent N a+ currents. As observed in GC in culture, abundant secondary lysosomes wer e particularly evident in the regressing CL, suggesting a functional link b etween eNaCh activity and this form of cellular regression in vivo. Our res ults Identify eNaCh in ovarian endocrine cells and demonstrate that their e xpression is under the inhibitory control of hCG. Activation of eNaChs in l uteal cells, due to loss of gonadotropin support, may initiate a cascade of events leading to decreased CL function, a process that involves lysosomal activation and autophagy. These results imply that ovarian eNaChs are invo lved in the physiological demise of the temporary endocrine organ CL in the primate ovary during the menstrual cycle. Because commonly used drugs, inc luding phenytoin, target NaChs, these results may be of clinical relevance.