title: Modulation of GABA(A) receptor phosphorylation and membrane trafficking by phospholipase C-related inactive protein/protein phosphatase 1 and 2A signaling complex underlying brain-derived neurotrophic factor-dependent regulation of GABAergic inhibition.
abstract: Brain-derived neurotrophic factor (BDNF) modulates several distinct aspects of synaptic transmission, including GABAergic transmission. Exposure to BDNF alters properties of GABA(A) receptors and induces changes in the expression level at the cell surface. Although phospholipase C-related inactive protein-1 (PRIP-1) plays an important role in GABA(A) receptor trafficking and function, its role in BDNF-dependent modulation of these receptors, together with the role of PRIP-2, was investigated using neurons cultured from PRIP double knock-out mice. The BDNF-dependent inhibition of whole cell GABA-evoked currents observed in wild type neurons was not detected in neurons cultured from knock-out mice. Instead, a gradual increase in GABA-evoked currents in these neurons correlated with a gradual increase in phosphorylation of GABA(A) receptor beta3 subunit in response to BDNF. To characterize the specific role(s) that PRIP plays as components of underlying molecular machinery, we examined the recruitment of protein phosphatase(s) to GABA(A) receptors. We demonstrate that PRIP associates with phosphatases as well as with beta subunits. PRIP was found to colocalize with GABA(A) receptor clusters in cultured neurons and with recombinant GABA(A) receptors when co-expressed in HEK293 cells. Importantly, a peptide mimicking a domain of PRIP involved in binding to beta subunits disrupted the co-localization of these proteins in HEK293 cells and potently inhibited the BDNF-mediated attenuation of GABA(A) receptor currents in wild type neurons. Together, the results suggest that PRIP plays an important role in BDNF-dependent regulation of GABA(A) receptors by mediating the specific association between beta subunits of these receptors with protein phosphatases.
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanematsu
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yasunaga
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan; Department of Developmental Physiology, National Institute for Physiological Science, Okazaki 444-8585, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Mizoguchi
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kuratani
authors.affiliation: Department of Physiology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Josef T
authors.initials: JT
authors.lastname: Kittler
authors.affiliation: Department of Pharmacology, School of Pharmacy, Brunswick Square, London, WC1N 1AX, United Kingdom.
authors.forename: Jasmina N
authors.initials: JN
authors.lastname: Jovanovic
authors.affiliation: Department of Biochemistry, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Takenaka
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Fukami
authors.affiliation: Department of Biochemistry, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Tadaomi
authors.initials: T
authors.lastname: Takenawa
authors.affiliation: Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.affiliation: Department of Developmental Physiology, National Institute for Physiological Science, Okazaki 444-8585, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nabekura
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: hirata1@dent.kyushu-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Hirata
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D004594:Electrophysiology; D018756:GABA Antagonists; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D018756:GABA Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; C513987:PRIP-1 phospholipase C-related protein, mouse; D021122:Protein Subunits; D011963:Receptors, GABA-A; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1