Altered regulation of potassium and calcium channels by GABA(B) and adenosine receptors in hippocampal neurons from mice lacking G alpha(o)

Altered regulation of potassium and calcium channels by GABA(B) and adenosi ne receptors in hippocampal neurons from mice lacking G alpha(o). J. Neurop hysiol. 83: 1010-1018, 2000. To examine the role of G(o) in modulation of i on channels by neurotransmitter receptors, we characterized modulation of i onic currents in hippocampal CA3 neurons from mice lacking both isoforms of G alpha(o). In CA3 neurons from G alpha(o)(-/-) mice, 2-chloro-adenosine a nd the GABA(B)-receptor agonist baclofen activated inwardly rectifying K+ c urrents and inhibited voltage-dependent Ca2+ currents just as effectively a s in G alpha(o)(+/+) littermates. However, the kinetics of transmitter acti on were dramatically altered in G alpha(o)(-/-) mice in that recovery on wa shout of agonist was much slower. For example, recovery from 2-chloro-adeno sine inhibition of calcium current was more than fourfold slower in neurons from G alpha(o)(+/+) mice [time constant of 12.0 +/- 0.8 (SE) s] than in n eurons from Ga-o(+/+) mice (time constant of 2.6 +/- 0.2 s). Recovery from baclofen effects was affected similarly. In neurons from control mice, effe cts of both baclofen and 2-chloro-adenosine on Ca2+ currents and K+ current s were abolished by brief exposure to external N-ethyl-maleimide (NEM). In neurons lacking G alpha(o), some inhibition of Ca2+ currents by baclofen re mained after NEM treatment, whereas baclofen activation of K+ currents and both effects of 2-chloro-adenosine were abolished. These results show that modulation of Ca2+ and K+ currents by G protein-coupled receptors in hippoc ampal neurons does not have an absolute requirement for G alpha(o). However , modulation is changed in the absence of G alpha(o) in having much slower recovery kinetics. A likely possibility is that the very abundant G alpha(o ) is normally used but, when absent, can readily be replaced by G proteins with different properties.