title: Calcium-modulating cyclophilin ligand regulates membrane trafficking of postsynaptic GABA(A) receptors.
abstract: 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.
authors.affiliation: Department of Biology, Penn State University, Life Sciences Building, University Park, PA 16802, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Yuan
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: David
authors.initials: D
authors.lastname: Norris
authors.forename: David D
authors.initials: DD
authors.lastname: Tran
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bram
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.forename: Bernhard
authors.initials: B
authors.lastname: Luscher
mesh_terms: 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
chemical_list: 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