Distinct regulation of beta2 and beta3 subunit-containing cerebellar synaptic GABAA receptors by calcium/calmodulin-dependent protein kinase II.
Modulation of GABA(A) receptor function and inhibitory synaptic transmission by phosphorylation has profound consequences for the control of synaptic plasticity and network excitability. We have established that activating alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMK-II) in cerebellar granule neurons differentially affects populations of IPSCs that correspond to GABA(A) receptors containing different subtypes of beta subunit. By using transgenic mice, we ascertained that alpha-CaMK-II increased IPSC amplitude but not the decay time by acting via beta2 subunit-containing GABA(A) receptors. In contrast, IPSC populations whose decay times were increased by alpha-CaMK-II were most likely mediated by beta3 subunit-containing receptors. Expressing alpha-CaMK-II with mutations that affected kinase function revealed that Ca(2+) and calmodulin binding is crucial for alpha-CaMK-II modulation of GABA(A) receptors, whereas kinase autophosphorylation is not. These findings have significant consequences for understanding the role of synaptic GABA(A) receptor heterogeneity within neurons and the precise regulation of inhibitory transmission by CaMK-II phosphorylation.
Houston
Catriona M
CM
Department of Pharmacology, University College London, London, United Kingdom.
Hosie
Alastair M
AM
Smart
Trevor G
TG
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D021122:Protein Subunits / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013997:Time Factors; D014162:Transfection / Q000379:methods
D021122:Protein Subunits; D011963:Receptors, GABA-A; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium