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Received September 22, 2002
Accepted after revision November 5, 2002
1 Department of Pharmacology and Therapeutics, Room 1317, McIntyre Medical Sciences Building, McGill University, 3655 Sir William Osler Promenade, Montreal, Quebec, Canada
2 Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island 02912, USA
3 Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
4 Instrumentation and Computer Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
* To whom correspondence should be addressed. E-mail: dbowie{at}pharma.mcgill.ca.
A diverse range of accessory proteins regulates the behaviour of most ligand- and voltage-gated ion channels. For glutamate receptor (GluR)6 kainate receptors, two unrelated proteins, concanavalin-A (Con-A) and postsynaptic density protein 95 (PSD-95), bind to extra- and intracellular domains, respectively, but are reported to exert similar effects on GluR6 desensitization behaviour. We have tested the hypothesis that distinct allosteric binding sites control GluR6 receptors via a common transduction pathway. Rapid agonist application to excised patches revealed that neither Con-A nor PSD-95 affect the onset of desensitization. The rate of desensitization elicited by 10 mM L-glutamate was similar in control (
fast = 5.5 ± 0.4 ms), Con-A-treated patches (fast = 6.1 ± 0.5 ms) and patches containing PSD-95 and GluR6 receptors (fast = 4.7 ± 0.6 ms). Likewise, the time course of recovery from GluR6 desensitization was similar in both control and Con-A conditions, whereas PSD-95 accelerated recovery almost twofold. Peak and steady-state (SS) dose-response relationships to glutamate were unchanged by lectin treatment (e.g. Control, EC50(SS) = 31 ± 28 µM vs Con-A, EC50(SS) = 45 ± 9 µM, n = 6), suggesting that Con-A does not convert non-conducting channels with high agonist affinity into an open conformation. Instead, we demonstrate that the effects of Con-A on macroscopic responses reflect a shift in the relative contribution of different open states of the channel. In contrast, the effect of PSD-95 on recovery behaviour suggests that the association between kainate receptors and cytoskeletal proteins regulates signalling at glutamatergic synapses. Our results show that Con-A and PSD-95 regulate kainate receptors via distinct allosteric mechanisms targeting selective molecular steps in the transduction pathway.
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