Distinct Regulation of β2 and β3 Subunit-Containing Cerebellar Synaptic GABA_AReceptors by Calcium/Calmodulin-Dependent Protein Kinase II

Abstract

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 ␣-calcium/calmodulin-dependent protein kinase II (␣-CaMK-II) in cerebellar granule neurons differentially affects populations of IPSCs that correspond to GABA A receptors containing different subtypes of ␤ subunit. By using transgenic mice, we ascertained that ␣-CaMK-II increased IPSC amplitude but not the decay time by acting via ␤2 subunit-containing GABA A receptors. In contrast, IPSC populations whose decay times were increased by ␣-CaMK-II were most likely mediated by ␤3 subunit-containing receptors. Expressing ␣-CaMK-II with mutations that affected kinase function revealed that Ca 2ϩ and calmodulin binding is crucial for ␣-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.

Increased Expression of Calcium/Calmodulin-Dependent Protein Kinase Type II Subunit Delta after Rat Traumatic Brain Injury

“…The different isoforms assemble into homo-or heteromultimeric holoenzymes composed of eight to twelve subunits (Chang et al 2007). In rat brain, four different subunits of the kinase have been identified: α, β, γ, and δ. CaMKII expression is controlled in part by tissue-specific gene expression: αCaM-KII is restricted to the central nervous system (Chen et al 2008;Houston et al 2008), while β, γ, and δ CaMKIIs occur in both neuronal and non-neuronal cell types from yeast to man, including a wide variety of pancreatic, leukemic, breast, and other tumor cells (Tombes et al 1999;Rochlitz et al 2000;Nozawa et al 2004). CaMKII was originally described in rat brain tissue.…”

Extracellular Signal-regulated Kinase and Glycogen Synthase Kinase 3β Regulate Gephyrin Postsynaptic Aggregation and GABAergic Synaptic Function in a Calpain-dependent Mechanism

“…3 Several protein kinases are known to modulate GABAergic transmission by affecting GABA A R channel gating properties or cell surface trafficking (7,8). Similar mechanisms also operate at glycinergic synapses, where, for instance, phosphorylation of a specific residue in the glycine receptor ␤ subunit affects surface mobility and synaptic function (9).…”

GABAA Receptor Expression in the Forebrain of Ataxic Rolling Nagoya Mice

“…Ca V 2.1 channels are distributed widely throughout the mammalian central nervous system [33]. The rationale for this study was derived from the regulation of GABA A receptor subunits by Ca 2+ influx [15][16][17][18][19] and that striatal dysfunction contributing to ataxia may result from GABAergic changes in the forebrain.…”

“…The rationale for the present study is based on the functional link between neuronal Ca 2+ influx and GABA A receptor subunit expression [15][16][17][18][19]. In the cerebellum, the loss of GABAergic inhibition may decrease tonic inhibition in cerebellar granule cells (CGCs), leading to ataxia in Angelman syndrome [20].…”