Gonadotropin-releasing Hormone Neurons Express K(ATP) Channels That Are Regulated by Estrogen and Responsive to Glucose and Metabolic Inhibition

Overview

Journal J Neurosci

Specialty Neurology

Date 2007 Sep 21

PMID 17881521

Citations 77

Authors

Chunguang Zhang

Martha A Bosch

Jon E Levine

Oline K Ronnekleiv

Martin J Kelly

Affiliations

Soon will be listed here.

Abstract

Gonadotropin-releasing hormone (GnRH) is released in a pulsatile manner that is dependent on circulating 17beta-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.

Citing Articles

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References

Liss B, Bruns R, Roeper J . Alternative sulfonylurea receptor expression defines metabolic sensitivity of K-ATP channels in dopaminergic midbrain neurons. EMBO J. 1999; 18(4):833-46. PMC: 1171176. DOI: 10.1093/emboj/18.4.833. View

Muroya S, Yada T, Shioda S, Takigawa M . Glucose-sensitive neurons in the rat arcuate nucleus contain neuropeptide Y. Neurosci Lett. 1999; 264(1-3):113-6. DOI: 10.1016/s0304-3940(99)00185-8. View

Reimann F, Ashcroft F . Inwardly rectifying potassium channels. Curr Opin Cell Biol. 1999; 11(4):503-8. DOI: 10.1016/S0955-0674(99)80073-8. View

Dhahan N, Moreau C, Prost A, Jacquet H, Alekseev A, Terzic A . Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP. Proc Natl Acad Sci U S A. 1999; 96(21):12162-7. PMC: 18429. DOI: 10.1073/pnas.96.21.12162. View

Shindo T, Katayama Y, Horio Y, Kurachi Y . MCC-134, a novel vascular relaxing agent, is an inverse agonist for the pancreatic-type ATP-sensitive K(+) channel. J Pharmacol Exp Ther. 1999; 292(1):131-5. View

Suter K, Song W, Sampson T, Wuarin J, Saunders J, Dudek F . Genetic targeting of green fluorescent protein to gonadotropin-releasing hormone neurons: characterization of whole-cell electrophysiological properties and morphology. Endocrinology. 1999; 141(1):412-9. DOI: 10.1210/endo.141.1.7279. View

Chappell P, Levine J . Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors. Endocrinology. 2000; 141(4):1477-85. DOI: 10.1210/endo.141.4.7428. View

Spanswick D, Smith M, Mirshamsi S, Routh V, Ashford M . Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci. 2000; 3(8):757-8. DOI: 10.1038/77660. View

Legan S, Coon G, Karsch F . Role of estrogen as initiator of daily LH surges in the ovariectomized rat. Endocrinology. 1975; 96(1):50-6. DOI: 10.1210/endo-96-1-50. View

10.

Ohkura S, Tanaka T, Nagatani S, Bucholtz D, Tsukamura H, Maeda K . Central, but not peripheral, glucose-sensing mechanisms mediate glucoprivic suppression of pulsatile luteinizing hormone secretion in the sheep. Endocrinology. 2000; 141(12):4472-80. DOI: 10.1210/endo.141.12.7853. View

11.

Ashcroft F, Gribble F . New windows on the mechanism of action of K(ATP) channel openers. Trends Pharmacol Sci. 2000; 21(11):439-45. DOI: 10.1016/s0165-6147(00)01563-7. View

12.

Miki T, Liss B, Minami K, Shiuchi T, Saraya A, Kashima Y . ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci. 2001; 4(5):507-12. DOI: 10.1038/87455. View

13.

Pfaffl M . A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29(9):e45. PMC: 55695. DOI: 10.1093/nar/29.9.e45. View

14.

Nunemaker C, DeFazio R, Geusz M, Herzog E, Pitts G, Moenter S . Long-term recordings of networks of immortalized GnRH neurons reveal episodic patterns of electrical activity. J Neurophysiol. 2001; 86(1):86-93. DOI: 10.1152/jn.2001.86.1.86. View

15.

Campbell R, ffrench-Mullen J, Cowley M, Smith M, Grove K . Hypothalamic circuitry of neuropeptide Y regulation of neuroendocrine function and food intake via the Y5 receptor subtype. Neuroendocrinology. 2001; 74(2):106-19. DOI: 10.1159/000054676. View

16.

Song Z, Levin B, McArdle J, Bakhos N, Routh V . Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes. 2001; 50(12):2673-81. DOI: 10.2337/diabetes.50.12.2673. View

17.

Liss B, Roeper J . A role for neuronal K(ATP) channels in metabolic control of the seizure gate. Trends Pharmacol Sci. 2001; 22(12):599-601; discussion 601-2. DOI: 10.1016/s0165-6147(00)01861-7. View

18.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

19.

Kuehl-Kovarik M, Pouliot W, Halterman G, Handa R, Dudek F, Partin K . Episodic bursting activity and response to excitatory amino acids in acutely dissociated gonadotropin-releasing hormone neurons genetically targeted with green fluorescent protein. J Neurosci. 2002; 22(6):2313-22. PMC: 6758266. View

20.

Matsumoto N, Komiyama S, Akaike N . Pre- and postsynaptic ATP-sensitive potassium channels during metabolic inhibition of rat hippocampal CA1 neurons. J Physiol. 2002; 541(Pt 2):511-20. PMC: 2290338. DOI: 10.1113/jphysiol.2002.018267. View