Plasmalemmal transport of magnesium in excitable cells

In excitable cells, the concentration of intracellular free Mg2+ ([Mg2+](i) ) is several hundred times lower than expected if Mg2+ ions were at electro chemical equilibrium. Since Mg2+ is a permeant ion across the plasmalemma, it must be constantly extruded. An ATP-dependent Na/Mg exchanger has been p roposed as the sole mechanism responsible for Mg2+ extrusion. However, this hypothesis fails to explain numerous observations including the fact that K+ and Cl- appear to be involved in Mg2+ transport. Until now three main li mitations have hampered the studies of plasmalemmal Mg2+ transport: i) Mg-2 8, the only useful radioactive isotope of Mg2+, has a short half-life and i s difficult to obtain; ii) squid giant axons, the ideal preparation to carr y out transport studies under "zero-trans" conditions, are only available d uring the summer months; and iii) the ionic fluxes mediated by the Mg2+ tra nsporter are very small and difficult to measure. The purpose of this manus cript is to review how these limitations have been recently overcame and to propose a novel hypothesis for the plasmalemmal Mg2+ transporter in squid axons and barnacle muscle cells. Overcoming the limitations for studying th e plasmalemmal Mg2+ transporter has been possible as a result of the follow ing findings: i) the Mg2+ exchanger can operate in "reverse", thus extracel lular Mg2+-dependent ionic fluxes (e.g., Na+ efflux) can be utilized to mea sure its activity; ii) internally perfused, voltage-clamped barnacle muscle cells which are available all year long can be used in addition to squid a xons; and iii) phosphoinositides (e.g., PIP2) produce an 8-fold increase in the ionic fluxes mediated by the Mg2+ exchanger. The hypothesis that we po stulate is that, in squid giant axons and barnacle muscle cells, a 2Na+ 2K 2Cl: 1Mg exchanger is responsible for transporting Mg2+ across the plasmal emma and for maintaining [Mg2+](i) under steady-state conditions.