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Ionic flow enhances low‐affinity binding: a revised mechanistic view into Mg 2+ block of NMDA receptors
Author(s) -
Yang YaChin,
Lee ChiaHsueh,
Kuo ChungChin
Publication year - 2010
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.178913
Subject(s) - biophysics , chemistry , ionic bonding , intracellular , ion , ligand gated ion channel , extracellular , ion channel , membrane potential , receptor , biochemistry , biology , organic chemistry
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.