Dependence of hormone secretion on activation-inactivation kinetics of voltage-sensitive Ca2+ channels in pituitary gonadotrophs.

Stojilković, Stanko S.; Iida, Tsuyoshi; Virmani, Ashraf; Rojas, Eduardo; Catt, Kevin J.

doi:10.1073/pnas.87.22.8855

Cited by 24 publications

(14 citation statements)

References 23 publications

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“…SA). Such a profile of Ca2+ response to depolarization by high K+ is consistent with the presence of L-type VSCCs and with changes in their activationinactivation kinetics to produce the biphasic type of response (15). In agreement with this mechanism, addition of nifedipine ( (Fig.…”

Section: Effects Of Ca2+ Channel Regulators On [Ca2+1 and Gnrhsupporting

confidence: 80%

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Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurons.

Krsmanović

Stojilković

Merelli

et al. 1992

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

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186

138

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Gonadotropin-releasing hormone (GnRH) is released episodically into the pituitary portal vessels and from hypothalamic tissue of male and female rats in vitro. Perfused primary cultures of rat hypothalamic neurons, as well as the GT1-1 GnRH neuronal cell line, spontaneously exhibited episodic GnRH secretion of comparable frequency to that observed with perifused hypothalami. Such pulsatile GnRH release from GT1 cells indicates that GnRH neurons generate rhythmic secretory activity in the absence of input from other cell types. In primary hypothalamic cultures, the frequency of GnRH pulses increased with the duration of culture. The spontaneous pulsatility in GnRH release was abolished in Ca2+-deficient medium and was markedly attenuated in the presence of nifedipine, an antagonist of voltage-sensitive Ca2' channels. The basal intracellular Ca2+ level of perifused GT1-1 cells cultured on coverslips was also dose-dependently reduced by nifedipine. Conversely, depolarization with high K+ increased intracellular Ca+ and GnRH release in an extracellular Ca2+-dependent and nifedipine-sensitive manner. The dihydropyridine Ca2+ channel agonist Bay K 8644 increased basal and K+-induced elevations of intracellular Ca2+ concentration and GnRH secretion. These findings demonstrate that pulsatile neuropeptide secretion is an intrinsic property of GnRH neuronal networks and is dependent on voltage-sensitive Ca2+ influx for its maintenance.The pulsatile secretion of gonadotropin-releasing hormone (GnRH) from hypothalamic nerve terminals adjacent to hypophyseal portal vessels in the median eminence is essential for the synthesis and secretion of gonadotropic hormones from the anterior pituitary gland (1). In contrast to other hypophysiotropic neurons, GnRH-producing cells are not concentrated in a discrete region of the hypothalamus but are distributed in the preoptic area and adjacent sites in the rostal portion of the hypothalamus (2). The majority of the GnRH neurons send projections to the median eminence and, despite their scattered locations, are interconnected to form a functional unit termed the GnRH pulse generator (3) that is responsible for the episodic release of GnRH and, consequently, of pituitary gonadotropins. Thus, pulses of luteinizing hormone secretion are elicited by preceding elevations of GnRH concentration in pituitary portal blood (4, 5), and a pulsatile mode of GnRH action is essential for the maintenance and control of normal gonadotropin profiles in the peripheral circulation (6).Changes in GnRH pulse frequency occur at puberty (7) and during the menstrual cycle (8), as well as after castration (9). Alterations in the pulsatile GnRH signal in several reproductive states may reflect a requirement not only for increased gonadotropin secretion but also for changes in the proportions of luteinizing hormone and follicle-stimulating hormone production under various physiological conditions. Thus, the pattern of GnRH secretion can differentially regulate the levels of gonadotropin subunit mRNAs in th...

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Section: Effects Of Ca2+ Channel Regulators On [Ca2+1 and Gnrhsupporting

confidence: 80%

“…First, activation of VSCCs by high K+-induced depolarization (15) in cultured hypothalamic neurons and GT1-1 neuronal cells leads to increased GnRH release, as in perifused hypothalamic explants (32,33 …”

Section: Discussionmentioning

confidence: 99%

Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurons.

Krsmanović

Stojilković

Merelli

et al. 1992

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

Self Cite

186

138

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“…Earlier studies have revealed that the kinetics of activation and inactivation of VGCCs underlines such a profile of [Ca 2ϩ ] i (Stojilkovic et al, 1990a). The addition of ET-1 during the sustained depolarization of cells induced a spike [Ca 2ϩ ] i response, but not inhibition of VGCI (Fig.…”

Section: Uncoupling Of Camentioning

confidence: 99%

Ca²⁺-Mobilizing Endothelin-A Receptors Inhibit Voltage-Gated Ca²⁺ Influx through G_i/oSignaling Pathway in Pituitary Lactotrophs

Tomić

Goor

et al. 2002

Mol Pharmacol

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In excitable cells, receptor-induced Ca 2ϩ release from intracellular stores is usually accompanied by sustained depolarization of cells and facilitated voltage-gated Ca 2ϩ influx (VGCI). In quiescent pituitary lactotrophs, however, endothelin-1 (ET-1) induced rapid Ca 2ϩ release without triggering Ca 2ϩ influx. Furthermore, in spontaneously firing and depolarized lactotrophs, the Ca 2ϩ -mobilizing action of ET-1 was followed by inhibition of spontaneous VGCI caused by prolonged cell hyperpolarization and abolition of action potential-driven Ca 2ϩ influx. Agonistinduced depolarization of cells and enhancement of VGCI upon Ca 2ϩ mobilization was established in both quiescent and firing lactotrophs treated overnight with pertussis toxin (PTX). Activation of adenylyl cyclase by forskolin and addition of cellpermeable 8-bromo-cAMP did not affect ET-1-induced sustained inhibition of VGCI, suggesting that the cAMP-protein kinase A signaling pathway does not mediate the inhibitory action of ET-1 on VGCI. Consistent with the role of PTX-sensitive K ϩ channels in ET-1-induced hyperpolarization of control cells, but not PTX-treated cells, ET-1 decreased the cell input resistance and activated a 5 mM Cs ϩ -sensitive K ϩ current. In the presence of Cs ϩ , ET-1 stimulated VGCI in a manner comparable with that observed in PTX-treated cells, whereas E-4031, a specific blocker of ether-a-go-go-related gene-like K ϩ channels, was ineffective. Similar effects of PTX and Cs ϩ were also observed in GH 3 immortalized cells transiently expressing ET A receptors. These results indicate that signaling of ET A receptors through the G i/o pathway in lactotrophs and the subsequent activation of inward rectifier K ϩ channels provide an effective and adenylyl cyclase-independent mechanism for a prolonged uncoupling of Ca 2ϩ mobilization and influx pathways.

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“…This can arise from estrogen modulation of synaptic inputs and/or intrinsic conductances that govern the excitability of GnRH neurons and hence the pulsatile release of the peptide (Leranth et al, 1985;Kalra, 1993;Herbison, 1998). Synchronized pulsatile activity may be intrinsic to GnRH neurons, because GT1-7 cells generate pulses of GnRH in the absence of exogenous input (Stojilkovic et al, 1990; Martínez de la Escalera et al, 1992;Wetsel et al, 1992). Also, acutely dissociated EGFP-GnRH neurons fire episodically in a relatively autonomous manner (Kuehl-Kovarik et al, 2002.…”

Section: Introductionmentioning

confidence: 99%

Gonadotropin-Releasing Hormone Neurons Express K_ATPChannels That Are Regulated by Estrogen and Responsive to Glucose and Metabolic Inhibition

Zhang¹,

Bosch²,

Levine³

et al. 2007

J. Neurosci.

112

139

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Gonadotropin-releasing hormone (GnRH) is released in a pulsatile manner that is dependent on circulating 17␤-estradiol (E2) and glucose concentrations. However, the intrinsic conductances responsible for the episodic firing pattern underlying pulsatile release and the effects of E2 and glucose on these conductances are primarily unknown. Whole-cell recordings from mouse enhanced green fluorescent protein-GnRH neurons revealed that the K ATP channel opener diazoxide induced an outward current that was antagonized by the sulfonylurea receptor 1 (SUR1) channel blocker tolbutamide. Single-cell reverse transcription (RT)-PCR revealed that the majority of GnRH neurons expressed Kir6.2 and SUR1 subunits, which correlated with the diazoxide/tolbutamide sensitivity. Also, a subpopulation of GnRH neurons expressed glucokinase mRNA, a marker for glucose sensitivity. Indeed, GnRH neurons decreased their firing in response to low glucose concentrations and metabolic inhibition. The maximum diazoxide-induced current was approximately twofold greater in E2-treated compared with oil-treated ovariectomized females. In current clamp, estrogen enhanced the diazoxide-induced hyperpolarization to a similar degree. However, based on quantitative RT-PCR, estrogen did not increase the expression of Kir6.2 or SUR1 transcripts in GnRH neurons. In the presence of ionotropic glutamate and GABA A receptor antagonists, tolbutamide depolarized and significantly increased the firing rate of GnRH neurons to a greater extent in E2-treated females. Finally, tolbutamide significantly increased GnRH secretion from the preoptic-mediobasal hypothalamus. Therefore, it appears that K ATP channels and glucokinase are expressed in GnRH neurons, which renders them directly responsive to glucose. In addition, K ATP channels are involved in modulating the excitability of GnRH neurons in an estrogen-sensitive manner that ultimately regulates peptide release.

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Dependence of hormone secretion on activation-inactivation kinetics of voltage-sensitive Ca2+ channels in pituitary gonadotrophs.

Cited by 24 publications

References 23 publications

Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurons.

Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurons.

Ca²⁺-Mobilizing Endothelin-A Receptors Inhibit Voltage-Gated Ca²⁺ Influx through G_i/oSignaling Pathway in Pituitary Lactotrophs

Gonadotropin-Releasing Hormone Neurons Express K_ATPChannels That Are Regulated by Estrogen and Responsive to Glucose and Metabolic Inhibition

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Dependence of hormone secretion on activation-inactivation kinetics of voltage-sensitive Ca2+ channels in pituitary gonadotrophs.

Cited by 24 publications

References 23 publications

Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurons.

Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurons.

Ca2+-Mobilizing Endothelin-A Receptors Inhibit Voltage-Gated Ca2+ Influx through Gi/oSignaling Pathway in Pituitary Lactotrophs

Gonadotropin-Releasing Hormone Neurons Express KATPChannels That Are Regulated by Estrogen and Responsive to Glucose and Metabolic Inhibition

Contact Info

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Ca²⁺-Mobilizing Endothelin-A Receptors Inhibit Voltage-Gated Ca²⁺ Influx through G_i/oSignaling Pathway in Pituitary Lactotrophs

Gonadotropin-Releasing Hormone Neurons Express K_ATPChannels That Are Regulated by Estrogen and Responsive to Glucose and Metabolic Inhibition