A novel serine kinase with specificity for beta 3-subunits is tightly associated with GABA(A) receptors

Tuning of gamma-aminobutyric acid type A (GABA(A)) receptor function via ph osphorylation 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 m odulatory role in vivo. However, no GABA(A) receptor-phospholylating kinase physically associated with the receptor has been identified so far on a mo lecular level. In this study, we demonstrate a GABA(A) receptor-associated protein serine kinase phosphorylating specifically beta 3-subunits of nativ e GABA(A) receptors. The characteristics of this novel kinase clearly disti nguish it from enzymatic activities that have been shown so far to phosphor ylate the GABA(A) receptor. We putatively identify this protein kinase as t he previously described GTAP34 (GABA(A) receptor-tubulin complex-associated protein of molecular mass 34 kDa). Using expressed recombinant fusion prot eins, we identify serine 408 as a major target of the phosphorylation react ion, whereas serine 407 is not phosphorylated. This demonstrates the high s pecificity of the kinase. Phosphorylation of serine 408 is known to result in a decreased receptor function. The direct association of this kinase wit h the receptor indicates an important physiological role.