Functional specificity of Gαq and Gα11 in the cholinergic and glutamatergic modulation of potassium currents and excitability in hippocampal neurons

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 M-3 receptors) and glutamate (via metabotropic glutamate receptor 5, mGluR(5)), 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 M-3 and mGluR(5) on sI(AHP). In the present study, we used mice deficient in the Galpha(q) and Galpha(11) genes to investigate the specific role of these G-protein alpha subunits in the cholinergic and glutamatergic modulation of sI(AHP) in CA1 neurons. In mice lacking Galphaq, the effects of muscarinic and glutamatergic agonists on sI(AHP) were nearly abolished, whereas beta-adrenergic agonists acting via Galpha(s) were still fully effective. Modulation of sI(AHP) by any of these agonists was instead unchanged in mice lacking Galpha(11). The additional depolarizing effects of muscarinic and glutamatergic agonists on CA1 neurons were preserved in mice lacking Galpha(q) or Galpha(11). Thus, Galpha(q), but not Galpha(11), 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 Galpha(q) and Galpha(11) in central neurons.