This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krsmanovic, L. Z. Articles by Catt, K. J. Search for Related Content PubMed PubMed Citation Articles by Krsmanovic, L. Z. Articles by Catt, K. J.

Muscarinic Regulation of Intracellular Signaling and Neurosecretion in Gonadotropin-Releasing Hormone Neurons

Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Kevin J. Catt, M.D., Ph.D., Endocrinology and Reproduction Research Branch, Building 49, Room 6A-36, NICHD, NIH, Bethesda, Maryland 20892. E-mail: catt{at}helix.nih.gov

Agonist activation of cholinergic receptors expressed in perifused hypothalamic and immortalized GnRH-producing (GT1–7) cells induced prominent peaks in GnRH release, each followed by a rapid decrease, a transient plateau, and a decline to below basal levels. The complex profile of GnRH release suggested that acetylcholine (ACh) acts through different cholinergic receptor subtypes to exert stimulatory and inhibitory effects on GnRH release. Whereas activation of nicotinic receptors caused a transient increase in GnRH release, activation of muscarinic receptors inhibited basal GnRH release. Nanomolar concentrations of ACh caused dose-dependent inhibition of cAMP production that was prevented by pertussis toxin (PTX), consistent with the activation of a plasma-membrane G_i protein. Micromolar concentrations of ACh also caused an increase in phosphoinositide hydrolysis that was inhibited by the M₁ receptor antagonist, pirenzepine. In ACh-treated cells, immunoblot analysis revealed that membrane-associated G_q/11 immunoreactivity was decreased after 5 min but was restored at later times. In contrast, immunoreactive G_i3 was decreased for up to 120 min after ACh treatment. The agonist-induced changes in G protein -subunits liberated during activation of muscarinic receptors were correlated with regulation of their respective transduction pathways. These results indicate that ACh modulates GnRH release from hypothalamic neurons through both M₁ and M₂ muscarinic receptors. These receptor subtypes are coupled to G_q and G_i proteins that respectively influence the activities of PLC and adenylyl cyclase/ion channels, with consequent effects on neurosecretion.

This article has been cited by other articles:

				L. Hu, K. Wada, N. Mores, L. Z. Krsmanovic, and K. J. Catt Essential Role of G Protein-gated Inwardly Rectifying Potassium Channels in Gonadotropin-induced Regulation of GnRH Neuronal Firing and Pulsatile Neurosecretion J. Biol. Chem., September 1, 2006; 281(35): 25231 - 25240. [Abstract] [Full Text] [PDF]

				K. Wada, L. Hu, N. Mores, C. E. Navarro, H. Fuda, L. Z. Krsmanovic, and K. J. Catt Serotonin (5-HT) Receptor Subtypes Mediate Specific Modes of 5-HT-Induced Signaling and Regulation of Neurosecretion in Gonadotropin-Releasing Hormone Neurons Mol. Endocrinol., January 1, 2006; 20(1): 125 - 135. [Abstract] [Full Text] [PDF]

				C.-M. Yeung, B.-S. An, C. K. Cheng, B. K.C. Chow, and P. C.K. Leung Expression and transcriptional regulation of the GnRH receptor gene in human neuronal cells Mol. Hum. Reprod., November 1, 2005; 11(11): 837 - 842. [Abstract] [Full Text] [PDF]

				S. A. Andric, D. Zivadinovic, A. E. Gonzalez-Iglesias, A. Lachowicz, M. Tomic, and S. S. Stojilkovic Endothelin-induced, Long Lasting, and Ca2+ Influx-independent Blockade of Intrinsic Secretion in Pituitary Cells by Gz Subunits J. Biol. Chem., July 22, 2005; 280(29): 26896 - 26903. [Abstract] [Full Text] [PDF]

				A. Cariboni, F. Pimpinelli, S. Colamarino, R. Zaninetti, M. Piccolella, C. Rumio, F. Piva, E. I. Rugarli, and R. Maggi The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons Hum. Mol. Genet., November 15, 2004; 13(22): 2781 - 2791. [Abstract] [Full Text] [PDF]

				V. Trkulja, V. Crljen-Manestar, H. Banfic, and Z. Lackovic Involvement of the Peripheral Cholinergic Muscarinic System in the Compensatory Ovarian Hypertrophy in the Rat Experimental Biology and Medicine, September 1, 2004; 229(8): 793 - 805. [Abstract] [Full Text] [PDF]

				L. Z. Krsmanovic, N. Mores, C. E. Navarro, K. K. Arora, and K. J. Catt An agonist-induced switch in G protein coupling of the gonadotropin-releasing hormone receptor regulates pulsatile neuropeptide secretion PNAS, March 4, 2003; 100(5): 2969 - 2974. [Abstract] [Full Text] [PDF]

				B. H. Shah, J.-W. Soh, and K. J. Catt Dependence of Gonadotropin-releasing Hormone-induced Neuronal MAPK Signaling on Epidermal Growth Factor Receptor Transactivation J. Biol. Chem., January 24, 2003; 278(5): 2866 - 2875. [Abstract] [Full Text] [PDF]

				M. Tomic', F. Van Goor, M.-L. He, D. Zivadinovic, and S. S. Stojilkovic Ca2+-Mobilizing Endothelin-A Receptors Inhibit Voltage-Gated Ca2+ Influx through Gi/o Signaling Pathway in Pituitary Lactotrophs Mol. Pharmacol., June 1, 2002; 61(6): 1329 - 1339. [Abstract] [Full Text] [PDF]

				D. Roy and D. D. Belsham Melatonin Receptor Activation Regulates GnRH Gene Expression and Secretion in GT1-7 GnRH Neurons. SIGNAL TRANSDUCTION MECHANISMS J. Biol. Chem., January 4, 2002; 277(1): 251 - 258. [Abstract] [Full Text]

				P. Berger, J. M. Tunon-De-Lara, J.-P. Savineau, and R. Marthan Signal Transduction in Smooth Muscle: Selected Contribution: Tryptase-induced PAR-2-mediated Ca2+ signaling in human airway smooth muscle cells J Appl Physiol, August 1, 2001; 91(2): 995 - 1003. [Abstract] [Full Text] [PDF]

				A. Charles, R. Weiner, and J. Costantin cAMP Modulates the Excitability of Immortalized Hypothalamic (GT1) Neurons via a Cyclic Nucleotide-Gated Channel Mol. Endocrinol., June 1, 2001; 15(6): 997 - 1009. [Abstract] [Full Text] [PDF]

				L. Z. Krsmanovic, N. Mores, C. E. Navarro, M. Tomic, and K. J. Catt Regulation of Ca2+-Sensitive Adenylyl Cyclase in Gonadotropin-Releasing Hormone Neurons Mol. Endocrinol., March 1, 2001; 15(3): 429 - 440. [Abstract] [Full Text]

				R. Maggi, F. Pimpinelli, L. Molteni, M. Milani, L. Martini, and F. Piva Immortalized Luteinizing Hormone-Releasing Hormone Neurons Show a Different Migratory Activity in Vitro Endocrinology, June 1, 2000; 141(6): 2105 - 2112. [Abstract] [Full Text] [PDF]

				B. Shi, G. Bhat, V. B. Mahesh, M. Brotto, T. M. Nosek, and D. W. Brann Bradykinin Receptor Localization and Cell Signaling Pathways Used by Bradykinin in the Regulation of Gonadotropin-Releasing Hormone Secretion Endocrinology, October 1, 1999; 140(10): 4669 - 4676. [Abstract] [Full Text]

				L. Z. Krsmanovic, A. J. Martinez-Fuentes, K. K. Arora, N. Mores, C. E. Navarro, H.-C. Chen, S. S. Stojilkovic, and K. J. Catt Autocrine Regulation of Gonadotropin-Releasing Hormone Secretion in Cultured Hypothalamic Neurons Endocrinology, March 1, 1999; 140(3): 1423 - 1431. [Abstract] [Full Text]

				Editorial: More Pieces of the Puzzle in Place, Even More Discovered Missing Endocrinology, October 1, 1998; 139(10): 4035 - 4035. [Abstract] [Full Text] [PDF]