Functional specificity of G alpha q and G alpha 11 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 Ca(2+)-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 Galpha(q), 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.
Krause
Michael
M
Max-Planck-Institute for Experimental Medicine, Department of Molecular Biology of Neuronal Signals, 37075 Göttingen, Germany..
Offermanns
Stefan
S
Stocker
Martin
M
Pedarzani
Paola
P
D000109:Acetylcholine / Q000378:metabolism*; D000318:Adrenergic beta-Agonists; D000818:Animals; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D018698:Glutamic Acid / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D021122:Protein Subunits; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D000318:Adrenergic beta-Agonists; D018690:Excitatory Amino Acid Agonists; D018721:Muscarinic Agonists; D021122:Protein Subunits; D018698:Glutamic Acid; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D000109:Acetylcholine; D011188:Potassium