The Journal of Neuroscience, June 20, 2007, 27(25):6800-6809; doi:10.1523/JNEUROSCI.0284-07.2007
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Cellular/Molecular
Na+/Cl Dipole Couples Agonist Binding to Kainate Receptor Activation
Adrian Y. C. Wong,
David M. MacLean, and
Derek Bowie
Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, Canada H3G 1Y6
Correspondence should be addressed to Dr. Derek Bowie, Department of Pharmacology and Therapeutics, McIntyre Medical Sciences Building, Room 1317, McGill University, 3655 Promenade Sir William Osler, Montreal, Québec, Canada H3G 1Y6. Email: derek.bowie{at}mcgill.ca
Kainate-selective ionotropic glutamate receptors (GluRs) require external Na+ and Cl as well as the neurotransmitter L-glutamate for activation. Although, external anions and cations apparently coactivate kainate receptors (KARs) in an identical manner, it has yet to be established how ions of opposite charge achieve this. An additional complication is that KARs are subject to other forms of cation modulation via extracellular acidification (i.e., protons) and divalent ions. Consequently, other cation species may compete with Na+ to regulate the time KARs remain in the open state. Here we designed experiments to unravel how external ions regulate GluR6 KARs. We show that GluR6 kinetics are unaffected by alterations in physiological pH but that divalent and alkali metal ions compete to determine the time course of KAR channel activity. Additionally, Na+ and Cl ions coactivate GluR6 receptors by establishing a dipole, accounting for their common effect on KARs. Using charged amino acids as tethered ions, we further demonstrate that the docking order is fixed with cations binding first, followed by anions. Together, our findings identify the dipole as a novel gating feature that couples neurotransmitter binding to KAR activation.
Key words: glutamate receptor; cation; anion; desensitization; gating; proton
Received Oct. 11, 2006;
revised May 17, 2007;
accepted May 18, 2007.
Correspondence should be addressed to Dr. Derek Bowie, Department of Pharmacology and Therapeutics, McIntyre Medical Sciences Building, Room 1317, McGill University, 3655 Promenade Sir William Osler, Montreal, Québec, Canada H3G 1Y6. Email: derek.bowie{at}mcgill.ca