GABA(B) receptor; trafficking; endocytosis; exocytosis; neuron; chronic pain
Zemoura K., Ralvenius W. T., Malherbe P., Benke D. (2016), The positive allosteric GABAB receptor modulator rac-BHFF enhances baclofen-mediated analgesia in neuropathic mice, in Neuropharmacology
, 108, 172-178.
Maier Patrick J, Zemoura Khaled, Acuña Mario A, Yévenes Gonzalo E, Zeilhofer Hanns Ulrich, Benke Dietmar (2014), Ischemia-like oxygen and glucose deprivation mediates down-regulation of cell surface γ-aminobutyric acidB receptors via the endoplasmic reticulum (ER) stress-induced transcription factor CCAAT/enhancer-binding protein (C/EBP)-homologous protein (CHOP)., in The Journal of Biological Chemistry
, 289(18), 12896-12907.
Zemoura Khaled, Benke Dietmar (2014), Proteasomal degradation of γ-aminobutyric acidB receptors is mediated by the interaction of the GABAB2 C terminus with the proteasomal ATPase Rtp6 and regulated by neuronal activity., in The Journal of Biological Chemistry
, 289(11), 7738-7746.
Zemoura Khaled, Schenkel Marisa, Acuña Mario A, Yévenes Gonzalo E, Zeilhofer Hanns Ulrich, Benke Dietmar (2013), Endoplasmic reticulum-associated degradation controls cell surface expression of γ-aminobutyric acid, type B receptors., in The Journal of biological chemistry
, 288(48), 34897-34905.
Benke Dietmar (2013), GABAB receptor trafficking and interacting proteins: targets for the development of highly specific therapeutic strategies to treat neurological disorders?, in Biochemical pharmacology
, 86(11), 1525-30.
Benke Dietmar, Zeilhofer Hanns Ulrich (2012), Divorce of obligatory partners in pain: disruption of GABA(B) receptor heterodimers in neuralgia., in The EMBO journal
, 31(15), 3234-6.
Benke Dietmar, Zemoura Khaled, Maier Patrick J (2012), Modulation of cell surface GABA(B) receptors by desensitization, trafficking and regulated degradation., in World Journal of Biological Chemistry
, 3(4), 61-72.
The metabotropic GABA(B) receptors mediate slow inhibitory neurotransmission and thereby regulate the excitability of neurons. They are abundantly expressed throughout the nervous system and have been implicated in several neurological disorders such as epilepsy, spasticity, addiction, schizophrenia, depression, anxiety and chronic pain. There is considerable evidence that trafficking mechanisms dynamically define cell surface expression of receptors and as a result regulate and integrate signal transduction. In addition, it is increasingly observed that receptor trafficking is affected in disease states. Studying the mechanisms of receptor trafficking under normal and pathological conditions has therefore a significant potential to raise concepts for the development of novel therapeutic strategies. The aim of this proposal is to understand the trafficking mechanisms that regulate cell surface expression of GABA(B) receptors in neurons derived from healthy and diseased animals. The research program is divided into four subprojects:In subproject 1 we intend to investigate how different aspects of GABA(B) receptor trafficking (endocytosis, recycling, sorting and degradation) are regulated by ubiquitination and how this is affected by neuronal activity. We expect that the results significantly advance our understanding how GABA(B) receptors contribute to neuronal plasticity.Subproject 2 addresses the physiological and pathological relevance of a mechanism (glutamate-induced down-regulation of GABA(B) receptors) that affects sorting of GABA(B) receptors. The results of this subproject will be pivotal to our understanding if and how GABA(B) receptor trafficking is regulated in the context of long-term potentiation, which is thought to underlie memory formation. Furthermore, we aim at analyzing the contribution of this mechanism to cell death as a consequence of ischemia. This has the potential to raise new ideas to interfere with glutamate-induced neuronal death.Subproject 3 tests the hypothesis that the interaction of GABA(B) receptors with a stress-induced protein (CHOP) down-regulates cell surface receptors and thereby contributes to the development or maintenance of diseases. This will be tested in an animal model of neuropathic pain and might provide the basis for the development of novel approaches to alleviate chronic pain states.In subproject 4 we intend to develop new methods that will enable us to investigate GABA(B) receptor trafficking in vivo. Currently, the analysis of receptor trafficking is predominantly restricted to cultured cells which prohibit the direct analysis of these mechanisms in animal models of diseases. We aim at developing two distinct methods: 1. a biochemical assay for the detection of cell surface receptors in eventually fixed brain slices with high spatial resolution and sensitivity at the single molecule level and 2. a method based on two-photon microscopy for real-time tracking of receptor dynamics in living brain slices and eventually living animals. The successful implementation of these new technologies is expected to advance the analysis of GABA(B) receptor trafficking to a further level.