title: Postsynaptic kainate receptor recycling and surface expression are regulated by metabotropic autoreceptor signalling.
abstract: Kainate receptors (KARs) play fundamentally important roles in controlling synaptic function and regulating neuronal excitability. Postsynaptic KARs contribute to excitatory neurotransmission but the molecular mechanisms underlying their activity-dependent surface expression are not well understood. Strong activation of KARs in cultured hippocampal neurons leads to the downregulation of postsynaptic KARs via endocytosis and degradation. In contrast, low-level activation augments postsynaptic KAR surface expression. Here, we show that this increase in KARs is due to enhanced recycling via the recruitment of Rab11-dependent, transferrin-positive endosomes into spines. Dominant-negative Rab11 or the recycling inhibitor primaquine prevents the kainate-evoked increase in surface KARs. Moreover, we show that the increase in surface expression is mediated via a metabotropic KAR signalling pathway, which is blocked by the protein kinase C inhibitor chelerythrine, the calcium chelator BAPTA and the G-protein inhibitor pertussis toxin. Thus, we report a previously uncharacterized positive feedback system that increases postsynaptic KARs in response to low- or moderate-level agonist activation and can provide additional flexibility to synaptic regulation.
authors.affiliation: School of Biochemistry, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK.
authors.forename: Inmaculada M
authors.initials: IM
authors.lastname: González-González
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Henley
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000378:metabolism*; D053119:Benzophenanthridines / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D025461:Feedback, Physiological; D006624:Hippocampus / Q000166:cytology; D007608:Kainic Acid / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D011319:Primaquine / Q000494:pharmacology; D021381:Protein Transport; D059748:Proteolysis; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000378:metabolism*; D015854:Up-Regulation; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000097806:GluK2 Kainate Receptor; D000099193:rab11 GTP-Binding Proteins
chemical_list: D017660:Autoreceptors; D053119:Benzophenanthridines; D004533:Egtazic Acid; D007608:Kainic Acid; D037342:Pertussis Toxin; D011319:Primaquine; D018092:Kainic Acid Receptors; D020691:rab GTP-Binding Proteins; D000097806:GluK2 Kainate Receptor; D000099193:rab11 GTP-Binding Proteins; C016299:chelerythrine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
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