title: Dependence of hormone secretion on activation-inactivation kinetics of voltage-sensitive Ca2+ channels in pituitary gonadotrophs.
abstract: The relationships between the activation status of voltage-sensitive Ca2+ channels and secretory responses were analyzed in perfused rat gonadotrophs during stimulation by high extracellular K+ concentration ([K+]e) or the physiological agonist, gonadotropin-releasing hormone (GnRH). Increase of [K+]e to 50 mM evokes an on-off secretory response, with a rapid rise in luteinizing hormone (LH) secretion to a peak at 35 sec (on response) followed by an exponential decrease to the steady-state level. Cessation of K+ stimulation elicits a transient (off) response followed by an exponential decrease to the basal level. The LH response to high [K+]e is nifedipine-sensitive and its amplitude depends on membrane potential. There is a close relationship between the LH secretory response to high [K+]e and the amplitude of the inward Ca2+ current measured at 100 msec in whole-cell patch clamp experiments. In addition, the profile of the LH secretory response is similar to that of the response of intracellular Ca2+ concentration ([Ca2+]i) in K(+)-stimulated cells. In Ca2(+)-deficient medium, the effect of high [K+]e is abolished; subsequent elevation of [Ca2+]e during the K+ pulse is followed by restoration of the on response, but with reduced magnitude. Agonist stimulation during the steady-state phase of the [K+]e pulse or after repetitive stimulation by high [K+]e elicited biphasic [Ca2+]i and secretory responses with a significantly reduced plateau phase; conversely, K(+)-induced LH release was reduced in cells treated with desensitizing doses of GnRH. These findings indicate that depolarization-induced changes in the status of voltage-sensitive Ca2+ channels determine the profiles of [Ca2+]i and LH responses to stimulation by high [K+]e; the initial activation of dihydropyridine-sensitive Ca2+ channels is clearly dependent on membrane potential, whereas their subsequent inactivation depends on increased [Ca2+]i. Such inactivation of voltage-sensitive Ca2+ channels also occurs during GnRH action and may represent an additional regulatory mechanism to limit the entry of extracellular Ca2+ during prolonged or frequent agonist stimulation.
authors.affiliation: Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
authors.forename: S S
authors.initials: SS
authors.lastname: Stojilković
authors.forename: T
authors.initials: T
authors.lastname: Iida
authors.forename: M A
authors.initials: MA
authors.lastname: Virmani
authors.forename: S
authors.initials: S
authors.lastname: Izumi
authors.forename: E
authors.initials: E
authors.lastname: Rojas
authors.forename: K J
authors.initials: KJ
authors.lastname: Catt
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D066298:In Vitro Techniques; D007986:Luteinizing Hormone / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D010903:Pituitary Gland, Anterior / Q000378:metabolism* / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
chemical_list: D015220:Calcium Channels; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D011188:Potassium; D002118:Calcium