Na+/Cl- dipole couples agonist binding to kainate receptor activation.
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.
Wong
Adrian Y C
AY
Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, Canada H3G 1Y6.
MacLean
David M
DM
Bowie
Derek
D
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008969:Molecular Sequence Data; D018092:Kainic Acid Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*
D002712:Chlorides; D018690:Excitatory Amino Acid Agonists; D018092:Kainic Acid Receptors; D012964:Sodium