Biomaterial Database

Modulation of GABAA receptor function by G protein-coupled 5-HT2C receptors. 1996

J P Huidobro-Toro, and C F Valenzuela, and R A Harris

Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.

Two classical neurotransmitters, 5-hydroxytryptamine (5-HT) and GABA, coexist in neurons of the medulla oblongata, and activation of 5-HT receptors modulates GABAA receptor function in neurons of the ventral tegmental area, substantia nigra and cerebellum. We now report that activation of 5-HT2C receptors produces a long-lasting (20-90 min) inhibition of GABAA receptors in Xenopus oocytes coexpressing both types of receptors 5-HT2C receptors caused a approximately 60% decrease in the GABAA receptor Emax without affecting the EC50 or Hill coefficient. Intracellular microinjection of 500 microM BAPTA blocked, whereas microinjection of inositol 1,4,5-triphosphate mimicked the inhibitory action of 5-HT2C receptors. The inhibition was independent of the GABAA receptors subunit composition; receptors containing alpha 2 beta 1, alpha 1 beta 1 gamma 2L, and alpha 2 beta 1 gamma 2S were inhibited to the same extent by 5-HT2C receptor activation. Moreover, GABAA receptors composed of wild-type alpha 2 plus mutant beta 1(S409A) subunits were inhibited to the same extent as wild-type receptors. The nonspecific protein kinase inhibitor, staurosporine, and the inhibitor of serine/threonine protein phosphatases, calyculin A, did not block the inhibitory effects of 5-HT2C receptors. The results with these inhibitors, taken together with those obtained with GABAA receptors with different subunit compositions, suggest that protein kinases or serine/threonine phosphatases are not involved in this GABAA receptor modulatory process. Thus, we propose that 5-HT2C receptors inhibit GABAA receptors by a Ca(2+)-dependent, but phosphorylation independent, mechanism and that 5-HT and GABA may act as cotransmitters to regulate neuronal activity. Furthermore, disruption of the cross-talk between these receptors may play a role in the anti-anxiety actions of 5-HT2 receptor antagonists.

UI	MeSH Term	Description	Entries
D008387	Marine Toxins	Toxic or poisonous substances elaborated by marine flora or fauna. They include also specific, characterized poisons or toxins for which there is no more specific heading, like those from poisonous FISHES.	Marine Biotoxins,Phycotoxins
D009865	Oocytes	Female germ cells derived from OOGONIA and termed OOCYTES when they enter MEIOSIS. The primary oocytes begin meiosis but are arrested at the diplotene state until OVULATION at PUBERTY to give rise to haploid secondary oocytes or ova (OVUM).	Ovocytes,Oocyte,Ovocyte
D010080	Oxazoles	Five-membered heterocyclic ring structures containing an oxygen in the 1-position and a nitrogen in the 3-position, in distinction from ISOXAZOLES where they are at the 1,2 positions.	Oxazole,1,3-Oxazolium-5-Oxides,Munchnones,1,3 Oxazolium 5 Oxides
D010749	Phosphoprotein Phosphatases	A group of enzymes removing the SERINE- or THREONINE-bound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992)	Phosphoprotein Phosphatase,Phosphoprotein Phosphohydrolase,Protein Phosphatase,Protein Phosphatases,Casein Phosphatase,Ecto-Phosphoprotein Phosphatase,Nuclear Protein Phosphatase,Phosphohistone Phosphatase,Phosphoprotein Phosphatase-2C,Phosphoseryl-Protein Phosphatase,Protein Phosphatase C,Protein Phosphatase C-I,Protein Phosphatase C-II,Protein Phosphatase H-II,Protein-Serine-Threonine Phosphatase,Protein-Threonine Phosphatase,Serine-Threonine Phosphatase,Threonine Phosphatase,Ecto Phosphoprotein Phosphatase,Phosphatase C, Protein,Phosphatase C-I, Protein,Phosphatase C-II, Protein,Phosphatase H-II, Protein,Phosphatase, Casein,Phosphatase, Ecto-Phosphoprotein,Phosphatase, Nuclear Protein,Phosphatase, Phosphohistone,Phosphatase, Phosphoprotein,Phosphatase, Phosphoseryl-Protein,Phosphatase, Protein,Phosphatase, Protein-Serine-Threonine,Phosphatase, Protein-Threonine,Phosphatase, Serine-Threonine,Phosphatase, Threonine,Phosphatase-2C, Phosphoprotein,Phosphatases, Phosphoprotein,Phosphatases, Protein,Phosphohydrolase, Phosphoprotein,Phosphoprotein Phosphatase 2C,Phosphoseryl Protein Phosphatase,Protein Phosphatase C I,Protein Phosphatase C II,Protein Phosphatase H II,Protein Phosphatase, Nuclear,Protein Serine Threonine Phosphatase,Protein Threonine Phosphatase,Serine Threonine Phosphatase
D011963	Receptors, GABA-A	Cell surface proteins which bind GAMMA-AMINOBUTYRIC ACID and contain an integral membrane chloride channel. Each receptor is assembled as a pentamer from a pool of at least 19 different possible subunits. The receptors belong to a superfamily that share a common CYSTEINE loop.	Benzodiazepine-Gaba Receptors,GABA-A Receptors,Receptors, Benzodiazepine,Receptors, Benzodiazepine-GABA,Receptors, Diazepam,Receptors, GABA-Benzodiazepine,Receptors, Muscimol,Benzodiazepine Receptor,Benzodiazepine Receptors,Benzodiazepine-GABA Receptor,Diazepam Receptor,Diazepam Receptors,GABA(A) Receptor,GABA-A Receptor,GABA-A Receptor alpha Subunit,GABA-A Receptor beta Subunit,GABA-A Receptor delta Subunit,GABA-A Receptor epsilon Subunit,GABA-A Receptor gamma Subunit,GABA-A Receptor rho Subunit,GABA-Benzodiazepine Receptor,GABA-Benzodiazepine Receptors,Muscimol Receptor,Muscimol Receptors,delta Subunit, GABA-A Receptor,epsilon Subunit, GABA-A Receptor,gamma-Aminobutyric Acid Subtype A Receptors,Benzodiazepine GABA Receptor,Benzodiazepine Gaba Receptors,GABA A Receptor,GABA A Receptor alpha Subunit,GABA A Receptor beta Subunit,GABA A Receptor delta Subunit,GABA A Receptor epsilon Subunit,GABA A Receptor gamma Subunit,GABA A Receptor rho Subunit,GABA A Receptors,GABA Benzodiazepine Receptor,GABA Benzodiazepine Receptors,Receptor, Benzodiazepine,Receptor, Benzodiazepine-GABA,Receptor, Diazepam,Receptor, GABA-A,Receptor, GABA-Benzodiazepine,Receptor, Muscimol,Receptors, Benzodiazepine GABA,Receptors, GABA A,Receptors, GABA Benzodiazepine,delta Subunit, GABA A Receptor,epsilon Subunit, GABA A Receptor,gamma Aminobutyric Acid Subtype A Receptors
D011985	Receptors, Serotonin	Cell-surface proteins that bind SEROTONIN and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action.	5-HT Receptor,5-HT Receptors,5-Hydroxytryptamine Receptor,5-Hydroxytryptamine Receptors,Receptors, Tryptamine,Serotonin Receptor,Serotonin Receptors,Tryptamine Receptor,Tryptamine Receptors,Receptors, 5-HT,Receptors, 5-Hydroxytryptamine,5 HT Receptor,5 HT Receptors,5 Hydroxytryptamine Receptor,5 Hydroxytryptamine Receptors,Receptor, 5-HT,Receptor, 5-Hydroxytryptamine,Receptor, Serotonin,Receptor, Tryptamine,Receptors, 5 HT,Receptors, 5 Hydroxytryptamine
D002614	Chelating Agents	Chemicals that bind to and remove ions from solutions. Many chelating agents function through the formation of COORDINATION COMPLEXES with METALS.	Chelating Agent,Chelator,Complexons,Metal Antagonists,Chelators,Metal Chelating Agents,Agent, Chelating,Agents, Chelating,Agents, Metal Chelating,Antagonists, Metal,Chelating Agents, Metal
D004533	Egtazic Acid	A chelating agent relatively more specific for calcium and less toxic than EDETIC ACID.	EGTA,Ethylene Glycol Tetraacetic Acid,EGATA,Egtazic Acid Disodium Salt,Egtazic Acid Potassium Salt,Egtazic Acid Sodium Salt,Ethylene Glycol Bis(2-aminoethyl ether)tetraacetic Acid,Ethylenebis(oxyethylenenitrile)tetraacetic Acid,GEDTA,Glycoletherdiamine-N,N,N',N'-tetraacetic Acid,Magnesium-EGTA,Tetrasodium EGTA,Acid, Egtazic,EGTA, Tetrasodium,Magnesium EGTA
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man