Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA_A Receptor Modulators?

Figure 3

Functional crosstalk between G-protein coupled receptors (GPCRs) (which are present in the serotonin, dopamine, acetylcholine system) and GABA_A receptors is facilitated through multiple protein kinases and scaffold proteins. GABA_A receptor β and γ2 subunits are phosphorylated (P) by PKA and PKC upon the activation of individual GPCRs for dopamine and serotonin. PKA phosphorylation of GABA_A receptor β1 and β3 subunits is dependent upon AKAP150/79, which directly interacts with these receptor subunits. AKAP150/79 also binds inactive PKA composed of regulatory (R) and catalytic (C) subunits. In addition, PKC phosphorylates the receptor β1–3 and γ2 subunits. Upon the activation of the appropriate GPCR, PKC-mediated phosphorylation is facilitated by the direct (but independent) interaction of the receptor for activated C kinase (RACK-1) and the β isoform of PKC with the GABA_A receptor β1–3 subunits. RACK-1 facilitates functional regulation of GABA_A receptors by controlling the activity of PKC associated with these proteins. The GABA_A receptor γ2 subunit is also phosphorylated by Src, and this kinase is capable of binding to receptor β and γ2 subunits. Finally, the functional effects of phosphorylation are diverse and range from inhibitions to enhancements of GABA_A receptor activity, dependent upon the receptor subunit composition. Reprinted by permission from Elsevier, reprinted from [95].