RGS7/Gβ5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling

In the hippocampus, the inhibitory neurotransmitter GABA shapes the activity of the output pyramidal neurons and plays important role in cognition. Most of its inhibitory effects are mediated by signaling from GABAB receptor to the G protein-gated Inwardly-rectifying K+ (GIRK) channels. Here, we show that RGS7, in cooperation with its binding partner R7BP, regulates GABABR-GIRK signaling in hippocampal pyramidal neurons. Deletion of RGS7 in mice dramatically sensitizes GIRK responses to GABAB receptor stimulation and markedly slows channel deactivation kinetics. Enhanced activity of this signaling pathway leads to decreased neuronal excitability and selective disruption of inhibitory forms of synaptic plasticity. As a result, mice lacking RGS7 exhibit deficits in learning and memory. We further report that RGS7 is selectively modulated by its membrane anchoring subunit R7BP, which sets the dynamic range of GIRK responses. Together, these results demonstrate a novel role of RGS7 in hippocampal synaptic plasticity and memory formation. DOI: http://dx.doi.org/10.7554/eLife.02053.001

[1]  K. Martemyanov,et al.  Control of Striatal Signaling by G Protein Regulators , 2011, Front. Neuroanat..

[2]  Eric R. Kandel,et al.  Transgenic Mice Lacking NMDAR-Dependent LTD Exhibit Deficits in Behavioral Flexibility , 2008, Neuron.

[3]  P. Buchwald,et al.  Molecular organization of the complex between the muscarinic M3 receptor and the regulator of G protein signaling, Gbeta(5)-RGS7. , 2010, Biochemistry.

[4]  K. Martemyanov,et al.  The R7 RGS Protein Family: Multi-Subunit Regulators of Neuronal G Protein Signaling , 2009, Cell Biochemistry and Biophysics.

[5]  H. Lester,et al.  RGS proteins reconstitute the rapid gating kinetics of Gβγ-activated inwardly rectifying K+ channels , 1997 .

[6]  J. Roder,et al.  D-Serine Augments NMDA-NR2B Receptor-Dependent Hippocampal Long-Term Depression and Spatial Reversal Learning , 2008, Neuropsychopharmacology.

[7]  Masahiko Watanabe,et al.  Association of Rgs7/Gβ5 complexes with girk channels and GABAB receptors in hippocampal CA1 pyramidal neurons , 2013, Hippocampus.

[8]  D. Johnston,et al.  Constitutively Active G-Protein-Gated Inwardly Rectifying K+ Channels in Dendrites of Hippocampal CA1 Pyramidal Neurons , 2005, The Journal of Neuroscience.

[9]  W. Regehr,et al.  Short-term synaptic plasticity. , 2002, Annual review of physiology.

[10]  Christian Lüscher,et al.  G Protein-Coupled Inwardly Rectifying K+ Channels (GIRKs) Mediate Postsynaptic but Not Presynaptic Transmitter Actions in Hippocampal Neurons , 1997, Neuron.

[11]  Tingyu Li,et al.  Mechanisms of Hippocampal Long-Term Depression Are Required for Memory Enhancement by Novelty Exploration , 2012, The Journal of Neuroscience.

[12]  E. Kandel,et al.  A Role in Learning for SRF: Deletion in the Adult Forebrain Disrupts LTD and the Formation of an Immediate Memory of a Novel Context , 2006, Neuron.

[13]  D. Ulrich,et al.  GABAB receptors: synaptic functions and mechanisms of diversity , 2007, Current Opinion in Neurobiology.

[14]  J. Hepler,et al.  Cellular Regulation of RGS Proteins: Modulators and Integrators of G Protein Signaling , 2002, Pharmacological Reviews.

[15]  Zhifang Dong,et al.  Hippocampal long-term depression is required for the consolidation of spatial memory , 2010, Proceedings of the National Academy of Sciences.

[16]  S. J. Martin,et al.  Synaptic plasticity and memory: an evaluation of the hypothesis. , 2000, Annual review of neuroscience.

[17]  Abraham Kovoor,et al.  Gi Irks GIRKs , 2002, Neuron.

[18]  Maureen P. Boyle,et al.  Palmitoylation regulates plasma membrane–nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family , 2005, The Journal of cell biology.

[19]  D. Manahan‐Vaughan,et al.  Novelty acquisition is associated with induction of hippocampal long-term depression. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Masahiko Watanabe,et al.  RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area , 2007, Nature Neuroscience.

[21]  C. Lüscher,et al.  Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease , 2010, Nature Reviews Neuroscience.

[22]  Denise Manahan-Vaughan,et al.  Hippocampal long-term depression: master or minion in declarative memory processes? , 2007, Trends in Neurosciences.

[23]  W. Simonds,et al.  Nuclear localization of the G protein β5/R7–regulator of G protein signaling protein complex is dependent on R7 binding protein , 2010, Journal of neurochemistry.

[24]  R. Malenka,et al.  Hippocampal Long-Term Potentiation Suppressed by Increased Inhibition in the Ts65Dn Mouse, a Genetic Model of Down Syndrome , 2004, The Journal of Neuroscience.

[25]  K. Kaltenbronn,et al.  GIRK channel modulation by assembly with allosterically regulated RGS proteins , 2012, Proceedings of the National Academy of Sciences.

[26]  K. Martemyanov,et al.  RGS6/G&bgr;5 Complex Accelerates IKACh Gating Kinetics in Atrial Myocytes and Modulates Parasympathetic Regulation of Heart Rate , 2010, Circulation research.

[27]  M. Simon,et al.  Instability of GGL domain-containing RGS proteins in mice lacking the G protein beta-subunit Gbeta5. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Simon,et al.  Instability of GGL domain-containing RGS proteins in mice lacking the G protein β-subunit Gβ5 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  N. Bowery.  GABAB receptor: a site of therapeutic benefit. , 2006, Current opinion in pharmacology.

[30]  C. Stevens,et al.  Heterogeneity of Release Probability, Facilitation, and Depletion at Central Synapses , 1997, Neuron.

[31]  Brock F. Binkowski,et al.  Engineered Luciferase Reporter from a Deep Sea Shrimp Utilizing a Novel Imidazopyrazinone Substrate , 2012, ACS chemical biology.

[32]  Michael J. Rowan,et al.  Behavioural stress facilitates the induction of long-term depression in the hippocampus , 1997, Nature.

[33]  C. Lüscher,et al.  Epilepsy, Hyperalgesia, Impaired Memory, and Loss of Pre- and Postsynaptic GABAB Responses in Mice Lacking GABAB(1) , 2001, Neuron.

[34]  N. Lambert,et al.  Regulators of G-protein Signaling accelerate GPCR signaling kinetics and govern sensitivity solely by accelerating GTPase activity , 2010, Proceedings of the National Academy of Sciences.

[35]  Y. Smith,et al.  Postnatal induction and localization of R7BP, a membrane-anchoring protein for regulator of G protein signaling 7 family-Gβ5 complexes in brain , 2008, Neuroscience.

[36]  V. Uversky,et al.  Expression and Localization of RGS9-2/Gβ5/R7BP Complex In Vivo Is Set by Dynamic Control of Its Constitutive Degradation by Cellular Cysteine Proteases , 2007, The Journal of Neuroscience.

[37]  J. Hensler,et al.  GABAB Receptor-Positive Modulators: Brain Region-Dependent Effects , 2012, Journal of Pharmacology and Experimental Therapeutics.

[38]  Michael J. Rowan,et al.  Spatial exploration induces a persistent reversal of long-term potentiation in rat hippocampus , 1998, Nature.

[39]  K. Martemyanov,et al.  Macromolecular Composition Dictates Receptor and G Protein Selectivity of Regulator of G Protein Signaling (RGS) 7 and 9-2 Protein Complexes in Living Cells* , 2013, The Journal of Biological Chemistry.

[40]  G. Collingridge,et al.  GABAB autoreceptors regulate the induction of LTP , 1991, Nature.

[41]  R Lujan,et al.  Perisynaptic Location of Metabotropic Glutamate Receptors mGluR1 and mGluR5 on Dendrites and Dendritic Spines in the Rat Hippocampus , 1996, The European journal of neuroscience.

[42]  V. Slepak,et al.  Intramolecular interaction between the DEP domain of RGS7 and the Gbeta5 subunit. , 2007, Biochemistry.

[43]  K. Kaltenbronn,et al.  R7BP Augments the Function of RGS7·Gβ5 Complexes by a Plasma Membrane-targeting Mechanism* , 2006, Journal of Biological Chemistry.

[44]  B. Sjögren.  Regulator of G protein signaling proteins as drug targets: current state and future possibilities. , 2011, Advances in pharmacology.

[45]  K. Blumer,et al.  R9AP and R7BP: traffic cops for the RGS7 family in phototransduction and neuronal GPCR signaling. , 2009, Trends in pharmacological sciences.

[46]  K. Martemyanov,et al.  Type 5 G Protein β Subunit (Gβ5) Controls the Interaction of Regulator of G Protein Signaling 9 (RGS9) with Membrane Anchors* , 2011, The Journal of Biological Chemistry.

[47]  Mark J. Thomas,et al.  Gβ5 recruits R7 RGS proteins to GIRK channels to regulate the timing of neuronal inhibitory signaling , 2010, Nature Neuroscience.

[48]  Alon Chen,et al.  Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice , 2012, Proceedings of the National Academy of Sciences.

[49]  Stephen Maren.  Neurobiology of Pavlovian fear conditioning. , 2001, Annual review of neuroscience.

[50]  C. Epstein,et al.  Abnormal synaptic plasticity in the Ts1Cje segmental trisomy 16 mouse model of Down syndrome , 2005, Neuropharmacology.

[51]  Y. Jan,et al.  G protein-activated inwardly rectifying potassium channels mediate depotentiation of long-term potentiation , 2009, Proceedings of the National Academy of Sciences.

[52]  R. Luján,et al.  Molecular and Cellular Diversity of Neuronal G-Protein-Gated Potassium Channels , 2005, The Journal of Neuroscience.

[53]  B. Alger,et al.  GABAergic and developmental influences on homosynaptic LTD and depotentiation in rat hippocampus , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[54]  R. Zucker.  Short-term synaptic plasticity. , 1989 .

[55]  T. K. Harden,et al.  Crystal structure of the multifunctional Gβ5–RGS9 complex , 2008, Nature Structural &Molecular Biology.

[56]  Mark E. Anderson,et al.  RGS6, a Modulator of Parasympathetic Activation in Heart , 2010, Circulation research.

[57]  P. Slesinger,et al.  GABAB receptor coupling to G-proteins and ion channels. , 2010, Advances in pharmacology.

[58]  Kerry J Ressler,et al.  RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory , 2010, Proceedings of the National Academy of Sciences.

[59]  N. Kamasawa,et al.  Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons , 2012, Proceedings of the National Academy of Sciences.

[60]  D. Mohapatra,et al.  Regulator of G Protein Signaling 6 (RGS6) Protein Ensures Coordination of Motor Movement by Modulating GABAB Receptor Signaling* , 2011, The Journal of Biological Chemistry.

[61]  N. Lambert,et al.  The c-terminus of GRK3 indicates rapid dissociation of G protein heterotrimers. , 2009, Cellular signalling.

[62]  T. K. Best,et al.  GABAB-GIRK2-mediated signaling in Down syndrome. , 2010, Advances in pharmacology.