Structure-Function Relationship of Calcium Ion Channel Antagonists at the Pituitary Gonadotrope<sup>*</sup>

Conn, P. Michael; Rogers, Deloris C.; Seay, Sallie G.

doi:10.1210/endo-113-5-1592

Cited by 72 publications

(11 citation statements)

References 12 publications

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“…Although nimodipine can block very potently the effects of high K on GH cells, the drug weakly inhibits basal levels of hormone secretion or the effects of stimulatory peptides, like TRH (Conn, Rogers & Seay, 1983;Enyeart et al 1985). Likewise, therapeutic doses of dihydropyridines have little effect on the secretion of prolactin or growth hormone in vivo (Struthers, Millar, Beastall, McIntosh & Reid, 1983;Abadie, Gauville & Brisson, 1984;Isles, Baty & Dow, 1985).…”

Section: Discussionmentioning

confidence: 99%

Nimodipine block of calcium channels in rat anterior pituitary cells.

Cohen

McCarthy

1987

The Journal of Physiology

158

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SUMMARY1. Ca channels were studied in the GH4C1 clonal cell line derived from rat anterior pituitary cells. The whole-cell variation of the patch-electrode voltage-clamp technique was used.2. Two types of Ca channels were found. One type ('slowly inactivating' channels) is insensitive to changes in holding potential, does not inactivate during test pulses lasting several seconds, and deactivates very quickly upon repolarization. For holding potentials <-40 mV, a second type of Ca channel is available for opening. This population ('transient' channels) differs from the first type in that it activates at more negative potentials, inactivates rapidly with either Ca or Ba as the charge carrier, deactivates about 10 times more slowly upon repolarization, and is less selective for Ba over Cs.3. Nimodipine preferentially blocks the slowly inactivating channels. Block of these channels is time-and voltage-dependent, such that block is maximized by long depolarizations.4

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Section: Discussionmentioning

confidence: 99%

Nimodipine block of calcium channels in rat anterior pituitary cells.

Cohen

McCarthy

1987

The Journal of Physiology

158

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“…LH release has been shown to be partially or completely dependent on Ca2+ influx (2,19). This Ca2+ influx apparently involves L-type channels (19,28), although there is also some disagreement on this point (2,29). However, recent studies, which monitored LH release on a relatively rapid time base, indicated that L-channel blockers did not block an initial spike of LH release but did block subsequent release over an extended time course (19).…”

Section: Methodsmentioning

confidence: 99%

Gonadotropin-releasing hormone-induced Ca2+ transients in single identified gonadotropes require both intracellular Ca2+ mobilization and Ca2+ influx.

Shangold

Murphy

Miller

1988

Proc. Natl. Acad. Sci. U.S.A.

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We examIned the effects of gonadotropinreleasing hormone (GnRH) (10). We now report the use of these techniques to show that GnRH produces Ca2" transients in identified gonadotropes with a very characteristic and complex time course. The role of these transients in the control of gonadotropin release is discussed. MATERIALS AND METHODSCell Culture. Female 35-day-old Sprague-Dawley rats were decapitated, their pituitaries were removed, and adenohypophyses were dissected from neurohypophyses. Anterior pituitaries were then enzymatically dispersed for 20 min with 0.25% trypsin (bovine, type XII-S, Sigma) in a metabolic shaker at 370C. Cells were then filtered through organza cloth (Tetko, Elmsford, NY), diluted to 50 ml in medium 199 with Hanks' salts and L-glutamine (GIBCO), and centrifuged at 350 x g for 10 min. The supernatant was removed, and cells were resuspended by trituration through a Pasteur pipette in 5 ml ofmedium and then were plated on sterile, poly(L-lysine)-coated (10 ,ug/ml, Sigma) etched-grid coverslips (Bellco). The cell density was z'2.5 x 105 cells per coverslip. The cell yield was z4 x 105 cells per rat. Cells were incubated for 2 days in 60-mm Falcon culture dishes, with medium 199 containing 10% (vol/vol) heat-inactivated horse serum (GIBCO) and 2.5% (vol/vol) fetal bovine serum (GIBCO) and supplemented with penicillin (5 units/ml) and streptomycin (50 pg/ml), in a 5% C02/95% air atmosphere in a water-jacketed incubator at 370C.Identification of Isolated Gonadotropes. Sheep erythrocytes (Colorado Serum, Denver) were washed four times in 0.9o NaCl and conjugated to protein A (0.5 mg/ml, Sigma) with CrCl2 (0.2 mg/ml). After further washing, cells were then mixed with LH antiserum (1:5), guinea pig complement (1:10, GIBCO), and GnRH (100 nM, Peninsula Laboratories, San Carlos, CA).

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“…Related work also suggested that the mechanism forCa2*-dependent hor mone release of LH by gonadotrophs was mediated by an ion channel chemically distinct from that in smooth muscle [8], where action potentials play a prominent role in media tion of Ca2* entry. Therefore, it is clear that previous work, where GnRH-stimulated release of LH has been measured, is consistent with the view that conventional all-or-none ac tion potentials, as found in mammalian nerve and muscle cells, do not feature prominently in Ca2+ entry leading to gonadotrophin release.…”

Section: Voltage Fluctuations As a Mechanism O F Ca> Entry In Gonadotmentioning

confidence: 99%

Electrophysiological Recordings from Gonadotrophs

Mason

Waring²

1985

Neuroendocrinology

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The electrophysiological properties of gonadotrophs have been studied in vitro, using the ovine adenohypophyseal pars tuberalis as a naturally enriched source of this cell type. Trypsin-dispersed pars tuberalis cells maintained in primary tissue culture had a membrane potential of -72 ± 4 mV (mean ± SEM) and an input resistance of 314 ± 38 MΩ. Spontaneous action potentials were not observed; however, a single spike could be induced by depolarizing current injection. The hypophysiotrophic peptide gonadotrophin-releasing hormone (GnRH) increased membrane voltage fluctuations, but these fluctuations (± 5–10 mV) did not induce action potentials or changes in membrane potential or resistance. Power spectra obtained from analysis of this noise indicated that the fundamental event underlying GnRH action has a mean life-time of 38.4 ± 4.5 ms. The obervations that cells incubated in recording medium secreted luteinizing hormone in response to GnRH and that the GnRH-induced increase in voltage noise was inhibited by Ca²⁺ channel antagonists support the hypotheses (1) that gonadotrophin secretion is initiated by GnRH-induced Ca²⁺ channel activation and (2) that action potentials are not a prerequisite for gonadotrophin release.

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Structure-Function Relationship of Calcium Ion Channel Antagonists at the Pituitary Gonadotrope^*

Cited by 72 publications

References 12 publications

Nimodipine block of calcium channels in rat anterior pituitary cells.

Nimodipine block of calcium channels in rat anterior pituitary cells.

Gonadotropin-releasing hormone-induced Ca2+ transients in single identified gonadotropes require both intracellular Ca2+ mobilization and Ca2+ influx.

Electrophysiological Recordings from Gonadotrophs

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Structure-Function Relationship of Calcium Ion Channel Antagonists at the Pituitary Gonadotrope*

Cited by 72 publications

References 12 publications

Nimodipine block of calcium channels in rat anterior pituitary cells.

Nimodipine block of calcium channels in rat anterior pituitary cells.

Gonadotropin-releasing hormone-induced Ca2+ transients in single identified gonadotropes require both intracellular Ca2+ mobilization and Ca2+ influx.

Electrophysiological Recordings from Gonadotrophs

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Structure-Function Relationship of Calcium Ion Channel Antagonists at the Pituitary Gonadotrope^*