Mechanisms of GABA_A receptor endocytosis and recycling. Endocytosis by clathrin-coated vesicles requires adaptor complex-2 (AP-2) and clathrin binding to the receptor. AP-2 is specific for endocytosis of surface proteins including GABA_A receptors. First, AP-2 recognizes and binds to GABA_A receptors, then clathrin binds the complex and the receptor is internalized. Phosphorylation of GABA_A receptors can prevent AP-2 binding and subsequent internalization. Internalized receptors may be recycled back to the cell surface or degraded depending upon undefined intracellular signals. Protein kinases can alter many steps in the receptor trafficking process. For example, PKC phosphorylation can alter recycling of receptors, whereas PKA can increase surface expression of GABA_A receptors. Adaptor complex-1 (AP-1) transports newly synthesized receptors from the trans-Golgi reticulum to the cell surface. Many proteins are required for intracellular trafficking of GABA_A receptors. For example, GABA_A receptor-associated protein (GABARAP) is involved in trafficking of GABA_A receptors from the endoplasmic reticulum/Golgi complex towards the plasma membrane and possibly also in vesicle-mediated cycling between the plasma membrane and cytoplasmic pool of receptors. N-ethylmaleimide-sensitive factor (NSF) interacts with GABARAP and influences intracellular trafficking of GABA_A receptors. Gephyrin reduces the diffusion of GABA_A receptors from the membrane and facilitates their clustering at synapses. Protein linking integrin-associated protein to cytoskeleton-1 (Plic-1) is also involved in GABA_A receptor trafficking and facilitates surface expression of the receptors (see Chen and Olsen 2007 for review)