INHIBITION OF M-TYPE K-TYPE CA2+ CHANNELS BY THE HUMAN GONADOTROPIN-RELEASING-HORMONE RECEPTOR HETEROLOGOUSLY EXPRESSED IN ADULT NEURONS( AND N)

Gonadotropin-releasing hormone (GnRH) controls all aspects of reproduc tive function, GnRH is secreted by hypothalamic neurons and exerts its effects on the endocrine system through pituitary gonadotropes, while its effects on sexual receptivity are mediated by the central nervous system, The electrophysiological responses of central neurons to GnRH have shown both excitatory and inhibitory responses, but little is kn own about the mechanisms by which GnRH can change neuronal excitabilit y. The present study addresses the mechanisms whereby stimulation of t he human GnRH receptor changes neuronal excitability by using a combin ation of electrophysiological and heterologous expression techniques, Microinjection of in vitro transcribed cRNA coding for the human GnRH receptor into enzymatically dissociated adult rat superior cervical ga nglion neurons resulted in GnRH receptor expression, Activation of the GnRH receptor inhibited both M-type K+ and N-type Ca2+ channels, Inhi bition of M-type K+ channels was insensitive to pertussis toxin pretre atment and blocked by intracellular GDP beta S, Inhibition of Ca2+ cha nnels was slow in onset, voltage independent and insensitive to pertus sis toxin, Wash-out of GnRH resulted in an unusual transient reversal of tonic G-protein-mediated Ca2+ channel inhibition, Block of the N-ty pe Ca2+ channel with omega-conotoxin GVIA decreased Ca2+ current inhib ition from 43 to 15%, indicating that the N-type Ca2+ channel is an ef fector target. Ca2+ channel inhibition was completely abolished by inc luding a Ca2+ chelator in the patch pipette, Cell-attached macropatch experiments indicated that Ca2+ channel inhibition is mediated by a di ffusible second messenger. These results demonstrate that the human Gn RH receptor can inhibit M-type K+ and N-type Ca2+ channels when hetero logously expressed in adult rat neurons. Modulation of M-type K+ and N -type Ca2+ channels in central neurons which contain GnRH receptors is likely to contribute to the changes in neuronal excitability elicited by GnRH.