A Novel Serine Kinase with Specificity for β3-Subunits Is Tightly Associated with GABAA Receptors

Tuning of γ-aminobutyric acid type A (GABAA) receptor function via phosphorylation of the receptor potentially allows neurons to modulate their inhibitory input. Several kinases, both of the serine-threonine kinase and the tyrosine kinase families, have been proposed as candidates for such a modulatory role in vivo. However, no GABAAreceptor-phosphorylating kinase physically associated with the receptor has been identified so far on a molecular level. In this study, we demonstrate a GABAA receptor-associated protein serine kinase phosphorylating specifically β3-subunits of native GABAA receptors. The characteristics of this novel kinase clearly distinguish it from enzymatic activities that have been shown so far to phosphorylate the GABAA receptor. We putatively identify this protein kinase as the previously described GTAP34 (GABAA receptor-tubulin complex-associated protein of molecular mass 34 kDa). Using expressed recombinant fusion proteins, we identify serine 408 as a major target of the phosphorylation reaction, whereas serine 407 is not phosphorylated. This demonstrates the high specificity of the kinase. Phosphorylation of serine 408 is known to result in a decreased receptor function. The direct association of this kinase with the receptor indicates an important physiological role.