Metal ion effects on ion channel gating

Abstract

Metal ions affect ion channels either by blocking the current or by modifying the gating. In the present review we analyse the effects on the gating of voltage-gated channels. We show that the effects can be understood in terms of three main mechanisms. Mechanism A assumes screening of fixed surface charges. Mechanism B assumes binding to fixed charges and an associated electrostatic modification of the voltage sensor. Mechanism C assumes binding and an associated non electrostatic modification of the gating. To quantify the non-electrostatic effect we introduced a slowing factor, A. A fourth mechanism (D) is binding to the pore with a consequent pore block, and could be a special case of Mechanisms B or C. A further classification considers whether the metal ion affects a single site or multiple sites. Analysing the properties of these mechanisms and the vast number of studies of metal ion effects on different voltage-gated on channels we conclude that group 2 ions mainly affect channels by classical screening (a version of Mechanism A). The transition metals and the Zn group ions mainly bind to the channel and electrostatically modify the gating (Mechanism B), causing larger shifts of the steady-state parameters than the group 2 ions, but also different shifts of activation and deactivation curves. The lanthanides mainly bind to the channel and both electrostatically and non-electrostatically modify the gating (Mechanisms B and C). With the exception of the ether-à-go-go-like channels, most channel types show remarkably similar ion-specific sensitivities.

Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1

“…We have previously identified charged residues that contribute to j out and to V 1/2 (13,15,48). However, we have not been able to completely transfer the effective surface charges from a metal-ion sensitive channel to a relatively metal ion-insensitive channel.…”

“…Based on the model of Gouy and Chapman (26,27), the Grahame equation (28) describes the relation between surface charge and surface potential in terms of the ionic composition of the solution. Even though this equation is based on the simplistic assumption of smeared surface charges it has been shown that it rather well describes the surface potential of a plane with moderately spread out point charges (29) and thus that of most ion channels (15). Approximating the Grahame equation, as shown in the Appendix, we obtain the following:…”

“…V 1/2 has been shown to depend on the existence of certain charged residues on the external surface of the channel protein (11)(12)(13), suggesting these charges contribute to an electric potential at the external surface (14)(15)(16). Metal ions were early recognized to alter the excitability of neurons by shifting the G(V) curve of ion channels along the voltage axis (17)(18)(19)(20).…”

“…Metal ions were early recognized to alter the excitability of neurons by shifting the G(V) curve of ion channels along the voltage axis (17)(18)(19)(20). For certain metal ions most of this effect is likely to be caused by screening (i.e., damping the electric field by mobile charges rather than by bound charges) of the critical negative charges at the external surface of the channel protein, modifying 4 out at the voltage sensor (14,15,20). Thus, such metal ions can be used as probes to explore the external surface potential.…”

“…This fact provides us with a tool to test the validity of the screening hypothesis. In our study we used the strontium ion (Sr 2þ ) as probe, because it seems to act exclusively via a screening mechanism; together with the magnesium ion (Mg 2þ ), it shifts the G(V) curve less than other tested metal ions, and activation time courses, deactivation time courses, gating currents, and G(V) curves are equally affected, as if these metal ions only alter the membrane voltage (11,15,21,22,(33)(34)(35)(36).…”