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The Journal of Neuroscience, February 1, 2002, 22(3):666-673

Functional Specificity of G_q and G₁₁ in the Cholinergic and Glutamatergic Modulation of Potassium Currents and Excitability in Hippocampal Neurons

Michael Krause¹, Stefan Offermanns², Martin Stocker^{1, 3}, and Paola Pedarzani^{1, 4}

¹ Max-Planck-Institute for Experimental Medicine, Department of Molecular Biology of Neuronal Signals, 37075 Göttingen, Germany, ² Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany, and ³ Wellcome Laboratory for Molecular Pharmacology, Department of Pharmacology, and ⁴ Department of Physiology, University College London, London WC1E 6BT, United Kingdom

In hippocampal and other cortical neurons, action potentials are followed by a slow afterhyperpolarization (sAHP) generated by the activation of small-conductance Ca²⁺-activated K⁺ channels and controlling spike frequency adaptation. The corresponding current, the apamin-insensitive sI_AHP, is a well known target of modulation by different neurotransmitters, including acetylcholine (via M₃ receptors) and glutamate (via metabotropic glutamate receptor 5, mGluR₅), in CA1 pyramidal neurons. The actions of muscarinic and mGluR agonists on sI_AHP involve the activation of pertussis toxin-insensitive G-proteins. However, the pharmacological tools available so far did not permit the identification of the specific G-protein subtypes transducing the effects of M₃ and mGluR₅ on sI_AHP. In the present study, we used mice deficient in the G_q and G₁₁ genes to investigate the specific role of these G-protein  subunits in the cholinergic and glutamatergic modulation of sI_AHP in CA1 neurons. In mice lacking G_q, the effects of muscarinic and glutamatergic agonists on sI_AHP were nearly abolished, whereas -adrenergic agonists acting via G_s were still fully effective. Modulation of sI_AHP by any of these agonists was instead unchanged in mice lacking G₁₁. The additional depolarizing effects of muscarinic and glutamatergic agonists on CA1 neurons were preserved in mice lacking G_q or G₁₁. Thus, G_q, but not G₁₁, mediates specifically the action of cholinergic and glutamatergic agonists on sI_AHP, without affecting the modulation of other currents. These results provide to our knowledge one of the first examples of the functional specificity of G_q and G₁₁ in central neurons.

Key words: G-protein; muscarinic; metabotropic glutamate; calcium-activated potassium current; afterhyperpolarization; CA1 pyramidal neurons

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Copyright © 2002 Society for Neuroscience  0270-6474/02/223666-08$05.00/0

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