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

Abstract

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 s/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 s/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 sub-types transducing the effects of M3 and mGluR5 on s/AHP. In the present study, we used mice deficient in the Gαq and Gα11 genes to investigate the specific role of these G-protein α subunits in the cholinergic and glutamatergic modulation of s/AHP in CA1 neurons. In mice lacking Gαq, the effects of muscarinic and glutamatergic agonists on s/AHP were nearly abolished, whereas β-adrenergic agonists acting via Gαs were still fully effective. Modulation of s/AHP by any of these agonists was instead unchanged in mice lacking Gα11. The additional depolarizing effects of muscarinic and glutamatergic agonists on CA1 neurons were preserved in mice lacking Gαq or Gα11. Thus, Gαq, but not Gα11, mediates specifically the action of cholinergic and glutamatergic agonists on s/AHP, without affecting the modulation of other currents. These results provide to our knowledge one of the first examples of the functional specificity of Gαq and Gα11 in central neurons.