Calcium-modulating cyclophilin ligand regulates membrane trafficking of postsynaptic GABA(A) receptors.
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.
Yuan
Xu
X
Department of Biology, Penn State University, Life Sciences Building, University Park, PA 16802, USA.
Yao
Jun
J
Norris
David
D
Tran
David D
DD
Bram
Richard J
RJ
Chen
Gong
G
Luscher
Bernhard
B
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D021983:Cyclophilins / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology*; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C490314:Caml protein, mouse; C546279:GABRG2 protein, human; C546280:Gabrg2 protein, mouse; D021122:Protein Subunits; D011963:Receptors, GABA-A; C081786:cyclophilin B; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D021983:Cyclophilins; D002118:Calcium