title: Ionic flow enhances low-affinity binding: a revised mechanistic view into Mg2+ block of NMDA receptors.
abstract: The N-methyl-d-aspartate receptor (NMDAR) channel is one of the major excitatory amino acid receptors in the mammalian brain. Since external Mg(2+) blocks the channel in an apparently voltage-dependent fashion, this ligand-gated channel displays intriguing voltage-dependent control of Na(+) and Ca(2+) permeability and thus plays an important role in synaptic physiology. We found that the essential features of Mg(2+) block could not be solely envisaged by binding of a charged blocker in the membrane electric field. Instead, the blocking effect of Mg(2+) is critically regulated by, and quantitatively correlated with, the relative tendency of outward and inward ionic fluxes. The 'intrinsic' affinity of Mg(2+) to the binding sites, however, is low (in the millimolar range) in the absence of net ionic flow at 0 mV. Besides, extracellular and intracellular Mg(2+) blocks the channel at distinct sites of electrical distances 0.7 and 0.95 from the outside, respectively. The two sites are separated by a high energy barrier for the movement of Mg(2+) (but not Na(+) or the other ions), and functionally speaking, each could accommodate 1.1 and 0.8 coexisting permeating ions, respectively. Mg(2+) block of the ionic flow thus is greatly facilitated by the flux-coupling effect or the ionic flow (the preponderant direction of permeant ion movement) per se, as if the poorly permeable Mg(2+) is 'pushed' against a high energy barrier by the otherwise permeating ions. Extracellular and intracellular Mg(2+) block then is in essence 'use dependent', more strongly inhibiting both Na(+) and Ca(2+) fluxes with stronger tendencies of influx and efflux, respectively. In conclusion, although permeant ions themselves could compete with Mg(2+), the flow or the tendency of movement of the permeant ions may actually enhance rather than interfere with Mg(2+) block, making the unique current-voltage relationship of NMDAR and the molecular basis of many important neurobiological phenomena.
authors.affiliation: Department of Life Science, Chang-Gung University, Tao-Yuan, Taiwan.
authors.forename: Ya-Chin
authors.initials: YC
authors.lastname: Yang
authors.forename: Chia-Hsueh
authors.initials: CH
authors.lastname: Lee
authors.forename: Chung-Chin
authors.initials: CC
authors.lastname: Kuo
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008274:Magnesium / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D050994:Voltage-Dependent Anion Channels / Q000502:physiology
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D050994:Voltage-Dependent Anion Channels; D008274:Magnesium