Accumulation of GABA(A) receptors (GABA(A)Rs) at GABAergic synapses requires the cytoplasmic loop region and C-terminal transmembrane domain of the receptor gamma2 subunit. We here report a novel interaction of gamma2 with Calcium-Modulating cyclophilin Ligand (CAML), an integral membrane protein that regulates this mechanism. Interaction of GABA(A)Rs with CAML depends on both the cytoplasmic region and fourth transmembrane domain of the gamma2 subunit, CAML immunoprecipitates with GABA(A)Rs from transfected cells and brain lysates and colocalizes with gamma2 in ER vesicles in soma and dendrites of neurons. CAML shRNA treatment results in reduced expression of postsynaptic GABA(A)Rs, along with significant reductions in GABA-evoked whole cell currents and GABAergic synaptic function, while glutamatergic transmission is unaffected. Reduced surface expression of GABA(A)Rs in CAML mutant neurons is associated with selective deficits in recycling of endocytosed GABA(A)Rs to the cell surface. Our results indicate a specific role of CAML in functional expression and endocytic recycling of postsynaptic GABA(A)Rs.
Keywords: calcium-modulating cyclophilin ligand; cyclophilin B; endocytic recycling; endoplasmic reticulum; exocytosis; inhibitory synapses; protein trafficking.