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Molecular Organization, Trafficking, and Degradation of the GABAB Receptor

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GABAB Receptor

Part of the book series: The Receptors ((REC,volume 29))

Abstract

GABAB receptors are heterodimeric G protein-coupled receptors composed of the two seven transmembrane spanning proteins GABAB1 and GABAB2. They are expressed in the vast majority of neurons and primarily regulate neuronal excitability via several distinct effector systems. There is evidence that GABAB receptors are organized in large macromolecular complexes composed of accessory and effector proteins to ensure efficient signaling. Communication through and regulation of GABAB receptors is determined by a constantly growing list of interacting proteins. In particular, trafficking events that regulate the cell surface availability of the receptors and thereby their signaling strength are controlled by protein–protein interactions that often convey posttranslational modifications such as phosphorylation or ubiquitination. Understanding the mechanisms regulating GABAB receptor availability is of major importance since it is increasingly recognized that aberrant regulation of GABAB receptor cell surface expression contributes to disease states including addiction, cerebral ischemia, and chronic pain. Here we briefly review our current understanding of the macromolecular structural organization of GABAB receptor complexes and the regulation of cell surface receptor availability by trafficking events and controlled receptor degradation.

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References

  • Beck, R., Rawet, M., Wieland, F. T., & Cassel, D. (2009). The COPI system: Molecular mechanisms and function. FEBS Letters, 583, 2701–2709.

    Article  CAS  PubMed  Google Scholar 

  • Benke, D., Honer, M., Michel, C., Bettler, B., & Mohler, H. (1999). Îł-Aminobutyric acid type B receptor splice variant proteins GBR1a and GBR1b are both associated with GBR2 in situ and display differential regional and subcellular distribution. Journal of Biological Chemistry, 274, 27323–27330.

    Article  CAS  PubMed  Google Scholar 

  • Bernard, P., Guedin, D., & Hibert, M. (2001). Molecular modeling of the GABA/GABAB receptor complex. Journal of Medicinal Chemistry, 44, 27–35.

    Article  CAS  PubMed  Google Scholar 

  • Biermann, B., Ivankova-Susankova, K., Bradaia, A., Abdel Aziz, S., Besseyrias, V., Kapfhammer, J. P., et al. (2010). The Sushi domains of GABAB receptors function as axonal targeting signals. Journal of Neuroscience, 30, 1385–1394.

    Article  CAS  PubMed  Google Scholar 

  • Binet, V., Brajon, C., Le Corre, L., Acher, F., Pin, J. P., & Prezeau, L. (2004). The heptahelical domain of GABAB2 is activated directly by CGP7930, a positive allosteric modulator of the GABAB receptor. Journal of Biological Chemistry, 279, 29085–29091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bischoff, S., Leonhard, S., Reymann, N., Schuler, V., Shigemoto, R., Kaupmann, K., et al. (1999). Spatial distribution of GABABR1 receptor mRNA and binding sites in the rat brain. Journal of Comparative Neurology, 412, 1–16.

    Article  CAS  PubMed  Google Scholar 

  • Brock, C., Boudier, L., Maurel, D., Blahos, J., & Pin, J. P. (2005). Assembly-dependent surface targeting of the heterodimeric GABAB receptor is controlled by COPI but not 14-3-3. Molecular Biology of the Cell, 16, 5572–5578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burkhard, P., Stetefeld, J., & Strelkov, S. V. (2001). Coiled coils: A highly versatile protein folding motif. Trends in Cell Biology, 11, 82–88.

    Article  CAS  PubMed  Google Scholar 

  • Burmakina, S., Geng, Y., Chen, Y., & Fan, Q. R. (2014). Heterodimeric coiled-coil interactions of human GABAB receptor. Proceedings of the National Academy of Sciences of the United States of America, 111, 6958–6963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calebiro, D., Rieken, F., Wagner, J., Sungkaworn, T., Zabel, U., Borzi, A., et al. (2013). Single-molecule analysis of fluorescently labeled G-protein-coupled receptors reveals complexes with distinct dynamics and organization. Proceedings of the National Academy of Sciences of the United States of America, 110, 743–748.

    Article  CAS  PubMed  Google Scholar 

  • Calver, A. R., Robbins, M. J., Cosio, C., Rice, S. Q. J., Babbs, A. J., Hirst, W. D., et al. (2001). The C-terminal domains of the GABAB receptor subunits mediate intracellular trafficking but are not required for receptor signaling. Journal of Neuroscience, 21, 1203–1210.

    CAS  PubMed  Google Scholar 

  • Ciechanover, A. (2006). Intracellular protein degradation: From a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Hematology American Society of Hematology. Education Program, 2006, 1–12.

    Google Scholar 

  • Cifuentes-Diaz, C., Marullo, S., & Doly, S. (2015). Anatomical and ultrastructural study of PRAF2 expression in the mouse central nervous system. Brain Structure and Function, doi:10.1007/s00429-015-1159-8.

    Google Scholar 

  • Comps-Agrar, L., Kniazeff, J., Brock, C., Trinquet, E., & Pin, J. P. (2012). Stability of GABAB receptor oligomers revealed by dual TR-FRET and drug-induced cell surface targeting. The FASEB Journal, 26, 3430–3439.

    Article  CAS  PubMed  Google Scholar 

  • Comps-Agrar, L., Kniazeff, J., Norskov-Lauritsen, L., Maurel, D., Gassmann, M., Gregor, N., et al. (2011). The oligomeric state sets GABAB receptor signalling efficacy. The EMBO Journal, 30, 2336–2349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Couve, A., Filippov, A. K., Connolly, C. N., Bettler, B., Brown, D. A., & Moss, S. J. (1998). Intracellular retention of recombinant GABAB receptors. Journal of Biological Chemistry, 273, 26361–26367.

    Article  CAS  PubMed  Google Scholar 

  • David, M., Richer, M., Mamarbachi, A. M., Villeneuve, L. R., Dupre, D. J., & Hebert, T. E. (2006). Interactions between GABAB1 receptors and Kir 3 inwardly rectifying potassium channels. Cellular Signalling, 18, 2172–2181.

    Article  CAS  PubMed  Google Scholar 

  • Doly, S., Shirvani, H., Gata, G., Meye, F. J., Emerit, M. B., Enslen, H., et al. (2015). GABAB receptor cell-surface export is controlled by an endoplasmic reticulum gatekeeper. Molecular Psychiatry, 21, 480–490.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dupuis, D. S., Relkovic, D., Lhuillier, L., Mosbacher, J., & Kaupmann, K. (2006). Point mutations in the transmembrane region of GABAB2 facilitate activation by the positive modulator N, N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) in the absence of the GABAB1 subunit. Molecular Pharmacology, 70, 2027–2036.

    Article  CAS  PubMed  Google Scholar 

  • Duthey, B., Caudron, S., Perroy, J., Bettler, B., Fagni, L., Pin, J. P., et al. (2002). A single subunit (GB2) is required for G-protein activation by the heterodimeric GABAB receptor. Journal of Biological Chemistry, 277, 3236–3241.

    Article  CAS  PubMed  Google Scholar 

  • Fairfax, B. P., Pitcher, J. A., Scott, M. G., Calver, A. R., Pangalos, M. N., Moss, S. J., et al. (2004). Phosphorylation and chronic agonist treatment atypically modulate GABAB receptor cell surface stability. Journal of Biological Chemistry, 279, 12565–12573.

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Alacid, L., Aguado, C., Ciruela, F., Martin, R., Colon, J., Cabanero, M. J., et al. (2009). Subcellular compartment-specific molecular diversity of pre- and post-synaptic GABA-activated GIRK channels in Purkinje cells. Journal of Neurochemistry, 110, 1363–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fritschy, J. M., Meskenaite, V., Weinmann, O., Honer, M., Benke, D., & Mohler, H. (1999). GABAB receptor splice variants GB1a and GB1b in rat brain: Developmental regulation, cellular distribution and extrasynaptic localization. The European Journal of Neuroscience, 11, 761–768.

    Article  CAS  PubMed  Google Scholar 

  • Gainetdinov, R. R., Premont, R. T., Bohn, L. M., Lefkowitz, R. J., & Caron, M. G. (2004). Desensitization of G protein-coupled receptors and neuronal functions. Annual Review of Neuroscience, 27, 107–144.

    Article  CAS  PubMed  Google Scholar 

  • Galvez, T., Duthey, B., Kniazeff, J., Blahos, J., Rovelli, G., Bettler, B., et al. (2001). Allosteric interactions between GB1 and GB2 subunits are required for optimal GABAB receptor function. The EMBO Journal, 20, 2152–2159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galvez, T., Parmentier, M. L., Joly, C., Malitschek, B., Kaupmann, K., Kuhn, R., et al. (1999). Mutagenesis and modeling of the GABAB receptor extracellular domain support a Venus flytrap mechanism for ligand binding. Journal of Biological Chemistry, 274, 13362–13369.

    Article  CAS  PubMed  Google Scholar 

  • Galvez, T., Prezeau, L., Milioti, G., Franek, M., Joly, C., Froestl, W., et al. (2000). Mapping the agonist-binding site of GABAB type 1 subunit sheds light on the activation process of GABAB receptors. Journal of Biological Chemistry, 275, 41166–41174.

    Article  CAS  PubMed  Google Scholar 

  • Gassmann, M., Haller, C., Stoll, Y., Aziz, S. A., Biermann, B., Mosbacher, J., et al. (2005). The RXR-type endoplasmic reticulum-retention/retrieval signal of GABAB1 requires distant spacing from the membrane to function. Molecular Pharmacology, 68, 137–144.

    CAS  PubMed  Google Scholar 

  • Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504, 254–259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geng, Y., Xiong, D., Mosyak, L., Malito, D. L., Kniazeff, J., Chen, Y., et al. (2012). Structure and functional interaction of the extracellular domain of human GABAB receptor GBR2. Nature Neuroscience, 15, 970–978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grabbe, C., Husnjak, K., & Dikic, I. (2011). The spatial and temporal organization of ubiquitin networks. Nature Reviews. Molecular Cell Biology, 12, 295–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grampp, T., Notz, V., Broll, I., Fischer, N., & Benke, D. (2008). Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABAB receptors in cortical neurons. Molecular and Cellular Neurosciences, 39, 628–637.

    Article  CAS  PubMed  Google Scholar 

  • Grampp, T., Sauter, K., Markovic, B., & Benke, D. (2007). Îł-Aminobutyric acid type B receptors are constitutively internalized via the clathrin-dependent pathway and targeted to lysosomes for degradation. Journal of Biological Chemistry, 282, 24157–24165.

    Article  CAS  PubMed  Google Scholar 

  • Guetg, N., Aziz, S. A., Holbro, N., Turecek, R., Rose, T., Seddik, R., et al. (2010). NMDA receptor-dependent GABAB receptor internalization via CaMKII phosphorylation of serine 867 in GABAB1. Proceedings of the National Academy of Sciences of the United States of America, 107, 13924–13929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hannan, S., Wilkins, M. E., Dehghani-Tafti, E., Thomas, P., Baddeley, S. M., & Smart, T. G. (2011). GABAB receptor internalisation is regulated by the R2 subunit. Journal of Biological Chemistry, 286, 24324–24335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hannan, S., Wilkins, M. E., & Smart, T. G. (2012). Sushi domains confer distinct trafficking profiles on GABAB receptors. Proceedings of the National Academy of Sciences of the United States of America, 109, 12171–12176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Havlickova, M., Prezeau, L., Duthey, B., Bettler, B., Pin, J. P., & Blahos, J. (2002). The intracellular loops of the GB2 subunit are crucial for G-protein coupling of the heteromeric Îł-aminobutyrateB receptor. Molecular Pharmacology, 62, 343–350.

    Google Scholar 

  • Hearing, M., Kotecki, L., Fernandez de Velasco, E., Fajardo-Serrano, A., Chung, H. J., Lujan, R., et al. (2013). Repeated cocaine weakens GABA-Girk signaling in layer 5/6 pyramidal neurons in the prelimbic cortex. Neuron, 80, 159–170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holter, J., Davies, J., Leresche, N., Crunelli, V., & Carter, D. A. (2005). Identification of two further splice variants of GABABR1 characterizes the conserved micro-exon 4 as a hot spot for regulated splicing in the rat brain. Journal of Molecular Neuroscience, 26, 99–108.

    Article  CAS  PubMed  Google Scholar 

  • Isomoto, S., Kaibara, M., Sakurai-Yamashita, Y., Nagayama, Y., Uezono, Y., Yano, K., et al. (1998). Cloning and tissue distribution of novel splice variants of the rat GABAB receptor. Biochemical and Biophysical Research Communications, 253, 10–15.

    Article  CAS  PubMed  Google Scholar 

  • Ivankova, K., Turecek, R., Fritzius, T., Seddik, R., Prezeau, L., Comps-Agrar, L., et al. (2013). Up-regulation of GABAB receptor signaling by constitutive assembly with the K+ channel tetramerization domain-containing protein 12 (KCTD12). Journal of Biological Chemistry, 288, 24848–24856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones, K. A., Borowsky, B., Tamm, J. A., Craig, D. A., Durkin, M. M., Dai, M., et al. (1998). GABAB receptor function as a heteromeric assembly of the subunits GABABR1 and GABABR2. Nature, 396, 674–679.

    Article  CAS  PubMed  Google Scholar 

  • Kammerer, R. A., Frank, S., Schulthess, T., Landwehr, R., Lustig, A., & Engel, J. (1999). Heterodimerization of a functional GABAB receptor is mediated by parallel coiled-coil alpha-helices. Biochemistry, 38, 13263–13269.

    Article  CAS  PubMed  Google Scholar 

  • Kantamneni, S., Gonzalez-Gonzalez, I. M., Luo, J., Cimarosti, H., Jacobs, S. C., Jaafari, N., et al. (2014). Differential regulation of GABAB receptor trafficking by different modes of N-methyl-D-aspartate (NMDA) receptor signaling. Journal of Biological Chemistry, 289, 6681–6694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kantamneni, S., Holman, D., Wilkinson, K. A., Correa, S. A., Feligioni, M., Ogden, S., et al. (2008). GISP binding to TSG101 increases GABAB receptor stability by down-regulating ESCRT-mediated lysosomal degradation. Journal of Neurochemistry, 107, 86–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaupmann, K., Huggel, K., Heid, J., Flor, P. J., Bischoff, S., Mickel, S. J., et al. (1997). Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors. Nature, 386, 239–246.

    Article  CAS  PubMed  Google Scholar 

  • Kaupmann, K., Malitschek, B., Schuler, V., Heid, J., Froestl, W., Beck, P., et al. (1998). GABAB receptor subtypes assemble into functional heteromeric complexes. Nature, 396, 683–687.

    Article  CAS  PubMed  Google Scholar 

  • Kniazeff, J., Galvez, T., Labesse, G., & Pin, J. P. (2002). No ligand binding in the GB2 subunit of the GABAB receptor is required for activation and allosteric interaction between the subunits. Journal of Neuroscience, 22, 7352–7361.

    CAS  PubMed  Google Scholar 

  • Kulik, A., Vida, I., Fukazawa, Y., Guetg, N., Kasugai, Y., Marker, C. L., et al. (2006). Compartment-dependent colocalization of Kir3.2-containing K+ channels and GABAB receptors in hippocampal pyramidal cells. Journal of Neuroscience, 26, 4289–4297.

    Article  CAS  PubMed  Google Scholar 

  • Kuramoto, N., Wilkins, M. E., Fairfax, B. P., Revilla-Sanchez, R., Terunuma, M., Tamaki, K., et al. (2007). Phospho-dependent functional modulation of GABAB receptors by the metabolic sensor AMP-dependent protein kinase. Neuron, 53, 233–247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laffray, S., Bouali-Benazzouz, R., Papon, M. A., Favereaux, A., Jiang, Y., Holm, T., et al. (2012). Impairment of GABAB receptor dimer by endogenous 14-3-3ζ in chronic pain conditions. The EMBO Journal, 31, 3239–3251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laffray, S., Tan, K., Dulluc, J., Bouali-Benazzouz, R., Calver, A. R., Nagy, F., et al. (2007). Dissociation and trafficking of rat GABAB receptor heterodimer upon chronic capsaicin stimulation. The European Journal of Neuroscience, 25, 1402–1416.

    Article  PubMed  Google Scholar 

  • Lahaie, N., Kralikova, M., Pr Eacutezeau, L., Blahos, J., & Bouvier, M. (2016). Post-endocytotic deubiquitination and degradation of the metabotropic Îł-aminobutyric acid receptor by the ubiquitin specific protease 14. Journal of Biological Chemistry, 291, 7156–7170.

    Article  CAS  PubMed  Google Scholar 

  • Laviv, T., Vertkin, I., Berdichevsky, Y., Fogel, H., Riven, I., Bettler, B., et al. (2011). Compartmentalization of the GABABreceptor signaling complex is required for presynaptic inhibition at hippocampal synapses. Journal of Neuroscience, 31, 12523–12532.

    Article  CAS  PubMed  Google Scholar 

  • Lecca, S., Pelosi, A., Tchenio, A., Moutkine, I., Lujan, R., Herve, D., et al. (2016). Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice. Nature Medicine, 22, 254–261.

    Article  CAS  PubMed  Google Scholar 

  • Lee, C., Mayfield, R. D., & Harris, R. A. (2010). Intron 4 containing novel GABAB1 isoforms impair GABAB receptor function. PLoS One, 5, e14044.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu, J., Maurel, D., Etzol, S., Brabet, I., Ansanay, H., Pin, J. P., et al. (2004). Molecular determinants involved in the allosteric control of agonist affinity in the GABAB receptor by the GABAB2 subunit. Journal of Biological Chemistry, 279, 15824–15830.

    Article  CAS  PubMed  Google Scholar 

  • Lujan, R., & Ciruela, F. (2012). GABAB receptors-associated proteins: Potential drug targets in neurological disorders? Current Drug Targets, 13, 129–144.

    Article  CAS  PubMed  Google Scholar 

  • Maier, P. J., Marin, I., Grampp, T., Sommer, A., & Benke, D. (2010). Sustained glutamate receptor activation down-regulates GABAB receptors by shifting the balance from recycling to lysosomal degradation. Journal of Biological Chemistry, 285, 35606–35614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maier, P. J., Zemoura, K., Acuna, M. A., Yevenes, G. E., Zeilhofer, H. U., & Benke, D. (2014). Ischemia-like oxygen and glucose deprivation mediates down-regulation of cell surface Îł-aminobutyric acidB receptors via the endoplasmic reticulum (ER) stress-induced transcription factor CCAAT/enhancer-binding protein (C/EBP)-homologous protein (CHOP). Journal of Biological Chemistry, 289, 12896–12907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malherbe, P., Masciadri, R., Norcross, R. D., Knoflach, F., Kratzeisen, C., Zenner, M. T., et al. (2008). Characterization of (R, S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one as a positive allosteric modulator of GABAB receptors. British Journal of Pharmacology, 154, 797–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malitschek, B., Ruegg, D., Heid, J., Kaupmann, K., Bittiger, H., Frostl, W., et al. (1998). Developmental changes of agonist affinity at GABABR1 receptor variants in rat brain. Molecular and Cellular Neurosciences, 12, 56–64.

    Article  CAS  PubMed  Google Scholar 

  • Marchese, A., Chen, C., Kim, Y. M., & Benovic, J. L. (2003). The ins and outs of G protein-coupled receptor trafficking. Trends in Biochemical Sciences, 28, 369–376.

    Article  CAS  PubMed  Google Scholar 

  • Margeta-Mitrovic, M., Jan, Y. N., & Jan, L. Y. (2000). A trafficking checkpoint controls GABAB receptor heterodimerization. Neuron, 27, 97–106.

    Article  CAS  PubMed  Google Scholar 

  • Margeta-Mitrovic, M., Jan, Y. N., & Jan, L. Y. (2001). Function of GB1 and GB2 subunits in G protein coupling of GABAB receptors. Proceedings of the National Academy of Sciences of the United States of America, 98, 14649–14654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maurel, D., Comps-Agrar, L., Brock, C., Rives, M. L., Bourrier, E., Ayoub, M. A., et al. (2008). Cell-surface protein-protein interaction analysis with time-resolved FRET and snap-tag technologies: Application to GPCR oligomerization. Nature Methods, 5, 561–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muller, C. S., Haupt, A., Bildl, W., Schindler, J., Knaus, H. G., Meissner, M., et al. (2010). Quantitative proteomics of the Cav2 channel nano-environments in the mammalian brain. Proceedings of the National Academy of Sciences of the United States of America, 107, 14950–14957.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mutneja, M., Berton, F., Suen, K. F., LĂĽscher, C., & Slesinger, P. A. (2005). Endogenous RGS proteins enhance acute desensitization of GABAB receptor-activated GIRK currents in HEK-293T cells. PflĂĽgers Archiv, 450, 61–73.

    Article  CAS  PubMed  Google Scholar 

  • Oyadomari, S., & Mori, M. (2004). Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death and Differentiation, 11, 381–389.

    Article  CAS  PubMed  Google Scholar 

  • Padgett, C. L., Lalive, A. L., Tan, K. R., Terunuma, M., Munoz, M. B., Pangalos, M. N., et al. (2012). Methamphetamine-evoked depression of GABAB receptor signaling in GABA neurons of the VTA. Neuron, 73, 978–989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pagano, A., Rovelli, G., Mosbacher, J., Lohmann, T., Duthey, B., Stauffer, D., et al. (2001). C-terminal interaction is essential for surface trafficking but not for heteromeric assembly of GABAB receptors. Journal of Neuroscience, 21, 1189–1202.

    CAS  PubMed  Google Scholar 

  • Park, H. W., Jung, H., Choi, K. H., Baik, J. H., & Rhim, H. (2011). Direct interaction and functional coupling between voltage-gated CaV1.3 Ca2+ channel and GABAB receptor subunit 2. FEBS Letters, 584, 3317–3322.

    Article  CAS  Google Scholar 

  • Perroy, J., Adam, L., Qanbar, R., ChĂ©nier, S., & Bouvier, M. (2003). Phosphorylation-independent desensitization of GABAB receptor by GRK4. The EMBO Journal, 22, 3816–3824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfaff, T., Malitschek, B., Kaupmann, K., Prezeau, L., Pin, J. P., Bettler, B., et al. (1999). Alternative splicing generates a novel isoform of the rat metabotropic GABABR1 receptor. The European Journal of Neuroscience, 11, 2874–2882.

    Article  CAS  PubMed  Google Scholar 

  • Pooler, A. M., Gray, A. G., & McIlhinney, R. A. (2009). Identification of a novel region of the GABAB2 C-terminus that regulates surface expression and neuronal targeting of the GABAB receptor. The European Journal of Neuroscience, 29, 869–878.

    Article  CAS  PubMed  Google Scholar 

  • Raiborg, C., & Stenmark, H. (2009). The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature, 458, 445–452.

    Article  CAS  PubMed  Google Scholar 

  • Ramirez, O. A., Vidal, R. L., Tello, J. A., Vargas, K. J., Kindler, S., Härtel, S., et al. (2009). Dendritic assembly of heteromeric Îł-aminobutyric acid type B receptor subunits in hippocampal neurons. Journal of Biological Chemistry, 284, 13077–13085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robbins, M. J., Calver, A. R., Filippov, A. K., Hirst, W. D., Russell, R. B., Wood, M. D., et al. (2001). GABAB2 is essential for G-protein coupling of the GABAB receptor heterodimer. Journal of Neuroscience, 21, 8043–8052.

    CAS  PubMed  Google Scholar 

  • Saftig, P., & Klumperman, J. (2009). Lysosome biogenesis and lysosomal membrane proteins: Trafficking meets function. Nature Reviews. Molecular Cell Biology, 10, 623–635.

    Article  CAS  PubMed  Google Scholar 

  • Sauter, K., Grampp, T., Fritschy, J. M., Kaupmann, K., Bettler, B., Mohler, H., et al. (2005). Subtype-selective interaction with the transcription factor CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) regulates cell surface expression of GABAB receptors. Journal of Biological Chemistry, 280, 33566–33572.

    Article  CAS  PubMed  Google Scholar 

  • Schwarz, D. A., Barry, G., Eliasof, S. D., Petroski, R. E., Conlon, P. J., & Maki, R. A. (2000). Characterization of Îł-aminobutyric acid receptor GABAB(1e), a GABAB(1) splice variant encoding a truncated receptor. Journal of Biological Chemistry, 275, 32174–32181.

    Article  CAS  PubMed  Google Scholar 

  • Schwenk, J., Metz, M., Zolles, G., Turecek, R., Fritzius, T., Bildl, W., et al. (2010). Native GABAB receptors are heteromultimers with a family of auxiliary subunits. Nature, 465, 231–235.

    Article  CAS  PubMed  Google Scholar 

  • Schwenk, J., Perez-Garci, E., Schneider, A., Kollewe, A., Gauthier-Kemper, A., Fritzius, T., et al. (2015). Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics. Nature Neuroscience, 19, 233–242.

    Article  PubMed  CAS  Google Scholar 

  • Seddik, R., Jungblut, S. P., Silander, O. K., Rajalu, M., Fritzius, T., Besseyrias, V., et al. (2012). Opposite effects of KCTD subunit domains on GABAB receptor-mediated desensitization. Journal of Biological Chemistry, 287, 39869–39877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith, M. H., Ploegh, H. L., & Weissman, J. S. (2011). Road to ruin: Targeting proteins for degradation in the endoplasmic reticulum. Science, 334, 1086–1090.

    Article  CAS  PubMed  Google Scholar 

  • Steiger, J. L., Bandyopadhyay, S., Farb, D. H., & Russek, S. J. (2004). cAMP response element-binding protein, activating transcription factor-4, and upstream stimulatory factor differentially control hippocampal GABABR1a and GABABR1b subunit gene expression through alternative promoters. Journal of Neuroscience, 24, 6115–6126.

    Article  CAS  PubMed  Google Scholar 

  • Sudo, Y., Hojo, M., Ando, Y., Takada, M., Murata, H., Kurata, S., et al. (2012). GABAB receptors do not internalize after baclofen treatment, possibly due to a lack of β-arrestin association: Study with a real-time visualizing assay. Synapse, 66, 759–769.

    Article  CAS  PubMed  Google Scholar 

  • Terunuma, M., Vargas, K. J., Wilkins, M. E., Ramirez, O. A., Jaureguiberry-Bravo, M., Pangalos, M. N., et al. (2010). Prolonged activation of NMDA receptors promotes dephosphorylation and alters postendocytic sorting of GABAB receptors. Proceedings of the National Academy of Sciences of the United States of America, 107, 13918–13923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian, X., Kang, D. S., & Benovic, J. L. (2014). β-Arrestins and G protein-coupled receptor trafficking. Handbook of Experimental Pharmacology, 219, 173–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tiao, J. Y., Bradaia, A., Biermann, B., Kaupmann, K., Metz, M., Haller, C., et al. (2008). The sushi domains of secreted GABAB1 isoforms selectively impair GABAB heteroreceptor function. Journal of Biological Chemistry, 283, 31005–31011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turecek, R., Schwenk, J., Fritzius, T., Ivankova, K., Zolles, G., Adelfinger, L., et al. (2014). Auxiliary GABAB receptor subunits uncouple G protein βγ subunits from effector channels to induce desensitization. Neuron, 82, 1032–1044.

    Article  CAS  PubMed  Google Scholar 

  • Urwyler, S., Mosbacher, J., Lingenhoehl, K., Heid, J., Hofstetter, K., Froestl, W., et al. (2001). Positive allosteric modulation of native and recombinant Îł-aminobutyric acidB receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501. Molecular Pharmacology, 60, 963–971.

    Google Scholar 

  • Urwyler, S., Pozza, M. F., Lingenhoehl, K., Mosbacher, J., Lampert, C., Froestl, W., et al. (2003). N, N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of Îł-aminobutyric acid B receptor function. Journal of Pharmacology and Experimental Therapeutics, 307, 322–330.

    Article  CAS  PubMed  Google Scholar 

  • Valdes, V., Valenzuela, J. I., Salas, D. A., Jaureguiberry-Bravo, M., Otero, C., Thiede, C., et al. (2012). Endoplasmic reticulum sorting and kinesin-1 command the targeting of axonal GABAB receptors. PLoS One, 7, e44168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valenzuela, J. I., Jaureguiberry-Bravo, M., Salas, D. A., Ramirez, O. A., Cornejo, V. H., Lu, H. E., et al. (2014). Transport along the dendritic endoplasmic reticulum mediates the trafficking of GABAB receptors. Journal of Cell Science, 127, 3382–3395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vargas, K. J., Terunuma, M., Tello, J. A., Pangalos, M. N., Moss, S. J., & Couve, A. (2008). The availability of surface GABAB receptors is independent of Îł-aminobutyric acid but controlled by glutamate in central neurons. Journal of Biological Chemistry, 283, 24641–24648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vembar, S. S., & Brodsky, J. L. (2008). One step at a time: Endoplasmic reticulum-associated degradation. Nature Reviews. Molecular Cell Biology, 9, 944–957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vigot, R., Barbieri, S., Bräuner-Osborne, H., Turecek, R., Shigemoto, R., Zhang, Y. P., et al. (2006). Differential compartmentalization and distinct functions of GABAB receptor variants. Neuron, 50, 589–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Villemure, J. F., Adam, L., Bevan, N. J., Gearing, K., Chenier, S., & Bouvier, M. (2005). Subcellular distribution of GABAB receptor homo- and hetero-dimers. Biochemical Journal, 388, 47–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, Q., Song, C., & Li, C. C. (2004). Molecular perspectives on p97-VCP: Progress in understanding its structure and diverse biological functions. Journal of Structural Biology, 146, 44–57.

    Article  CAS  PubMed  Google Scholar 

  • Wei, K. R., Eubanks, J. H., Francis, J., Jia, Z. P., & Snead, O. C. (2001a). Cloning and tissue distribution of a novel isoform of the rat GABABR1 receptor subunit. Neuroreport, 12, 833–837.

    Article  CAS  PubMed  Google Scholar 

  • Wei, K., Jia, Z., Wang, Y. T., Yang, J., Liu, C. C., & Snead, O. C., 3rd. (2001b). Cloning and characterization of a novel variant of rat GABABR1 with a truncated C-terminus. Brain Research. Molecular Brain Research, 89, 103–110.

    Article  CAS  PubMed  Google Scholar 

  • Weissman, A. M., Shabek, N., & Ciechanover, A. (2011). The predator becomes the prey: Regulating the ubiquitin system by ubiquitylation and degradation. Nature Reviews. Molecular Cell Biology, 12, 605–620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • White, J. H., Wise, A., Main, M. J., Green, A., Fraser, N. J., Disney, G. H., et al. (1998). Heterodimerization is required for the formation of functional GABAB receptors. Nature, 396, 679–682.

    Article  CAS  PubMed  Google Scholar 

  • Wilkins, M. E., Li, X., & Smart, T. G. (2008). Tracking cell surface GABAB receptors using an α-bungarotoxin tag. Journal of Biological Chemistry, 283, 34745–34752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Workman, E. R., Haddick, P. C., Bush, K., Dilly, G. A., Niere, F., Zemelman, B. V., et al. (2015). Rapid antidepressants stimulate the decoupling of GABAB receptors from GIRK/Kir3 channels through increased protein stability of 14-3-3η. Molecular Psychiatry, 20, 298–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zemoura, K., & Benke, D. (2014). Proteasomal degradation of Îł-aminobutyric acidB receptors is mediated by the interaction of the GABAB2 C terminus with the proteasomal ATPase Rtp6 and regulated by neuronal activity. Journal of Biological Chemistry, 289, 7738–7746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zemoura, K., Schenkel, M., Acuna, M. A., Yevenes, G. E., Zeilhofer, H. U., & Benke, D. (2013). Endoplasmic reticulum-associated degradation (ERAD) controls cell surface expression of Îł-aminobutyric acid, type B receptors. Journal of Biological Chemistry, 288, 34897–34905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, Z., Zhang, W., Huang, S., Sun, Q., Wang, Y., Hu, Y., et al. (2015). GABAB receptor promotes its own surface expression by recruiting a Rap1-dependent signaling cascade. Journal of Cell Science, 128, 2302–2313.

    Article  CAS  PubMed  Google Scholar 

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  1. Institute of Pharmacology and Toxicology, University of Zurich, CH-8057, Zurich, Switzerland

    Dietmar Benke, Karthik Balakrishnan & Khaled Zemoura

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  2. Karthik Balakrishnan
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  1. Neuroscience Institute, National Research Council of Italy Neuroscience Institute, Cagliari, Italy

    Giancarlo Colombo

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Benke, D., Balakrishnan, K., Zemoura, K. (2016). Molecular Organization, Trafficking, and Degradation of the GABAB Receptor. In: Colombo, G. (eds) GABAB Receptor. The Receptors, vol 29. Humana Press, Cham. https://doi.org/10.1007/978-3-319-46044-4_4

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