Intracellular trafficking of GABA(A) receptors

Some of the mechanisms that control the intracellular trafficking of GABA(A ) receptors have recently been described. Following the synthesis of alpha, beta, and gamma subunits in the endoplasmic reticulum, ternary receptor co mplexes assemble slowly and are inefficiently inserted into surface membran es of heterologous cells. While beta 3, beta 4, and gamma 2S subunits appea r to contain polypeptide sequences that alone are sufficient for surface ta rgeting, these sequences are neither conserved nor essential for surface ex pression of heteromeric GABA(A) receptors formed from alpha 1 beta or alpha 1 beta gamma subunits. At the neuronal surface, native GABA(A) receptor cl ustering and synaptic targeting require a gamma 2 subunit and the participa tion of gephyrin, a clustering protein for glycine receptors. A linker prot ein, such as the GABA(A) receptor associated protein (GABARAP), may be nece ssary for the formation of GABA(A) receptor aggregates containing gephyrin. A substantial fraction of surface receptors are sequestered by endocytosis , another process which apparently requires a GABA(A) receptor gamma 2 subu nit. In heterologous cells, constitutive endocytosis seems to predominate w hile, in cortical neurons, internalization is evoked when receptors are occ upied by GABA(A) agonists. After constitutive endocytosis, receptors are re latively stable and can be rapidly recycled to the cell surface, a process that may be regulated by protein kinase C. On the other hand, a portion of the intracellular GABA(A) receptors derived from ligand-dependent endocytos is is apparently degraded. The clustering of GABA(A) receptors at synapses and at coated pits are two mechanisms that may compete for a pool of diffus able receptors, providing a model for plasticity at inhibitory synapses.