期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 282, 期 24, 页码 17855-17865出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M611533200
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资金
- Medical Research Council [G0601529] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
- Medical Research Council [G0601529] Funding Source: researchfish
- MRC [G0601529] Funding Source: UKRI
Phosphorylation can affect both the function and trafficking of GABA(A) receptors with significant consequences for neuronal excitability. Serine/threonine kinases can phosphorylate the intracellular loops between M3-4 of GABA(A) receptor beta and gamma subunits thereby modulating receptor function in heterologous expression systems and in neurons (1, 2). Specifically, CaMK-II has been demonstrated to phosphorylate the M3 -4 loop of GABAA receptor subunits expressed as GST fusion proteins (3, 4). It also increases the amplitude of GABAA receptor-mediated currents in a number of neuronal cell types (5 -7). To identify which substrate sites CaMK-II might phosphorylate and the consequent functional effects, we expressed recombinant GABAA receptors in NG108-15 cells, which have previously been shown to support CaMK-II modulation of GABAA receptors containing the beta 3 subunit (8). We now demonstrate that CaMK-II mediates its effects on alpha 1 beta 3 receptors via phosphorylation of Ser(383) within the M3-4 domain of the beta subunit. Ablation of beta 3 subunit phosphorylation sites for CaMK-II revealed that for alpha beta gamma receptors, CaMK-II has a residual effect on GABA currents that is not mediated by previously identified sites of CaMK-II phosphorylation. This residual effect is abolished by mutation of tyrosine phosphorylation sites, Tyr(365) and Tyr(367), on the gamma 2S subunit, and by the tyrosine kinase inhibitor genistein. These results suggested that CaMK-II is capable of directly phosphorylating GABAA receptors and activating endogenous tyrosine kinases to phosphorylate the gamma 22 subunit in NG108-15 cells. These findings were confirmed in a neuronal environment by expressing recombinant GABAA receptors in cerebellar granule neurons.
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