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.
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.
Kanematsu
Takashi
T
Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan.
Yasunaga
Atsushi
A
Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan.
Mizoguchi
Yoshito
Y
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.
Kuratani
Akiko
A
Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka 812-8582, Japan.
Kittler
Josef T
JT
Department of Physiology, University College London, London WC1E 6BT, United Kingdom.
Jovanovic
Jasmina N
JN
Department of Pharmacology, School of Pharmacy, Brunswick Square, London, WC1N 1AX, United Kingdom.
Takenaka
Kei
K
Department of Biochemistry, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Nakayama
Keiichi I
KI
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Fukami
Kiyoko
K
Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
Takenawa
Tadaomi
T
Department of Biochemistry, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Moss
Stephen J
SJ
Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
Nabekura
Junichi
J
Department of Developmental Physiology, National Institute for Physiological Science, Okazaki 444-8585, Japan.
Hirata
Masato
M
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.
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
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