Neurobeachin Regulates Glutamate- and GABA-Receptor Targeting to Synapses via Distinct Pathways.
Neurotransmission and synaptic strength depend on expression of post-synaptic receptors on the cell surface. Post-translational modification of receptors, trafficking to the synapse through the secretory pathway, and subsequent insertion into the synapse involves interaction of the receptor with A-kinase anchor proteins (AKAPs) and scaffolding proteins. Neurobeachin (Nbea), a brain specific AKAP, is required for synaptic surface expression of both glutamate and GABA receptors. Here, we investigated the role of Nbea-dependent targeting of postsynaptic receptors by studying Nbea interaction with synapse-associated protein 102 (SAP102/Dlg3) and protein kinase A subunit II (PKA II). A Nbea mutant lacking the PKA binding domain showed a similar distribution as wild-type Nbea in Nbea null neurons and partially restored GABA receptor surface expression. To understand the relevance of Nbea interaction with SAP102, we analysed SAP102 null mutant mice. Nbea levels were reduced by ~80% in SAP102 null mice, but glutamatergic receptor expression was normal. A single-point mutation in the pleckstrin homology domain of Nbea (E2218R) resulted in loss of binding with SAP102. When expressed in Nbea null neurons, this mutant fully restored GABA receptor surface expression, but not glutamate receptor expression. Our results suggest that the PKA-binding domain is not essential for Nbea's role in receptor targeting and that Nbea targets glutamate and GABA receptors to the synapse via distinct molecular pathways by interacting with specific effector proteins.
Department of Functional Genomics, Centre for Neurogenomics and Cognitive Research (CNCR), Neuroscience Campus Amsterdam, VU Medical Centre, VU University Amsterdam, 1081HV, Amsterdam, The Netherlands.
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Farzana
Department of Functional Genomics, Centre for Neurogenomics and Cognitive Research (CNCR), Neuroscience Campus Amsterdam, VU Medical Centre, VU University Amsterdam, 1081HV, Amsterdam, The Netherlands.
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Zalm
Department of Molecular and Cellular Neurobiology, Centre for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, 1081HV, Amsterdam, The Netherlands.
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Chen
Department of Molecular and Cellular Neurobiology, Centre for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, 1081HV, Amsterdam, The Netherlands.
K W
KW
Li
Centre for Clinical Brain Sciences, Edinburgh University, Edinburgh, EH16 4SB, United Kingdom.
Seth G N
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Grant
Department of Molecular and Cellular Neurobiology, Centre for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, 1081HV, Amsterdam, The Netherlands.
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Smit
Department of Functional Genomics, Centre for Neurogenomics and Cognitive Research (CNCR), Neuroscience Campus Amsterdam, VU Medical Centre, VU University Amsterdam, 1081HV, Amsterdam, The Netherlands.
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Toonen
Department of Functional Genomics, Centre for Neurogenomics and Cognitive Research (CNCR), Neuroscience Campus Amsterdam, VU Medical Centre, VU University Amsterdam, 1081HV, Amsterdam, The Netherlands. m.verhage@vu.nl.|Department of Clinical Genetics, Centre for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU Medical Centre, VU University Amsterdam, Amsterdam, The Netherlands. m.verhage@vu.nl.
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Verhage
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051528:Guanylate Kinases / Q000172:deficiency / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D018079:Receptors, GABA / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission
D002352:Carrier Proteins; D008565:Membrane Proteins; C403265:Nbea protein, mouse; D009419:Nerve Tissue Proteins; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D017868:Cyclic AMP-Dependent Protein Kinases; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases
AKAP; GABA receptors; Glutamate receptors; Neurobeachin; SAP102; Synapse