Abstract
Hippocampal α7* nicotinic acetylcholine receptors modulate the release of GABA and glutamate. The control of functional receptor pools by cell firing or synaptic activity could therefore allow for a local adjustment of the sensitivity to cholinergic input upon changes in neuronal activity. We first investigated whether tonic depolarization or cell firing affected the function of α7*. The amplitude of α7*-gated whole-cell currents in cultured rat hippocampal neurons exposed to high-extracellular K+ (40 mM KCl) for 24 to 48 h increased 1.3 to 5.5 times. The proportion of α7*-responsive neurons (99%), the potency of acetylcholine, and the sensitivity to nicotinic antagonists were all unaffected. In contrast, block of spontaneous cell firing with tetrodotoxin for 24 h led to a 37% reduction in mean current amplitude. Reduced α7* responses were seen after a 24-h blockade of N-type calcium channels but not of L-type calcium channels, N-methyl-d-aspartate (NMDA), or non-NMDA receptor channels, protein kinase C, or calcium-calmodulin kinases II and IV. The N-type or L-type calcium channel antagonists ω-conotoxin GVIA and nifedipine did not prevent the current-potentiating effect of KCl. The GABAA antagonist picrotoxin led to a 44% reduction of the currents, despite increasing action potential firing, and also reversed the potentiating effect of KCl. Treatment with GABA, midazolam, or a GABA uptake blocker led to increased currents. These data indicate that α7*-gated currents in hippocampal neurons are regulated by GABAergic activity and suggest that depolarization-induced GABA release may underlie the effect of increased extracellular KCl.
Footnotes
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This work was supported by Pronex/Ministério da Ciência e Tecnologia Grants 1996 and 2003, Fundação Carlos Chagus Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, National Institutes of Health Grant NS41671, and the Finep-University of Maryland, Baltimore Molecular Pharmacology Training Program.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.106385.
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ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor(s); APV, d,l-2-amino-5-phosphonovalerate; DHβE, dihydro-β-erythroidine; DNQX, 6,7-dinitroquinoxaline-2,3(1H,4H)-dione; EC50, mean effective concentration; KN-62 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine; GF 109203X, bisindolylmaleimide I; NO-711, 1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride; MLA, methyllycaconitine; M-S, Mack-Skillings; NMG, N-methyl-d-glucamine; VDCCs, voltage-dependent calcium channels; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-d-aspartate; GAT, GABA transporter; TTX, tetrodotoxin; CNS, central nervous system; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione.
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↵1 Recipients of Conselho Nacional de Desenvolvimento Cientifico e Tecnológico fellowships.
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↵2 Recipients of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior fellowships.
- Received April 17, 2006.
- Accepted July 7, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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