Mechanism of magnesium activation of calcium-activated potassium channels

Abstract

Large-conductance (BK type) Ca(2+)-dependent K(+) channels are essential for modulating muscle contraction and neuronal activities such as synaptic transmission and hearing. BK channels are activated by membrane depolarization and intracellular Ca(2+) and Mg(2+) (refs 6-10). The energy provided by voltage, Ca(2+) and Mg(2+) binding are additive in activating the channel, suggesting that these signals open the activation gate through independent pathways. Here we report a molecular investigation of a Mg(2+)-dependent activation mechanism. Using a combined site-directed mutagenesis and structural analysis, we demonstrate that a structurally new Mg(2+)-binding site in the RCK/Rossman fold domain -- an intracellular structural motif that immediately follows the activation gate S6 helix -- is responsible for Mg(2+)-dependent activation. Mutations that impair or abolish Mg(2+) sensitivity do not affect Ca(2+) sensitivity, and vice versa. These results indicate distinct structural pathways for Mg(2+)- and Ca(2+)-dependent activation and suggest a possible mechanism for the coupling between Mg(2+) binding and channel opening.

Large conductance Ca2+-activated K+ (BK) channel: Activation by Ca2+ and voltage

“…Other divalent cations, such as Cd 2+ , Mn 2+ , Fe 2+, Co 2+ , and Ni 2+ , also were able to enhance activation and increase the Hill coefficient of channels already activated by Ca 2+ (Oberhauser et al, 1988). Recently, it was discovered that most of these cations are able to activate the BK channel in the absence of Ca 2+ by binding to a low affinity site (Shi and Cui, 2001;Zhang et al, 2001;Shi et al, 2002;Zeng et al, 2005).…”

“…These residues that are conserved in mSlo1 and dSlo1 but not in Slo3 were mutated to the corresponding amino acids present in Slo3 with the result that two hot spots were found, E374A and E399N ( Fig. 3C; Shi et al, 2002). Mutation of either of these two residues completely obliterated Mg 2+ -dependent activation.…”

A Rationally Designed, Spiropyran-Based Chemosensor for Magnesium

“…Magnesium ions (Mg 2+ ) play an important role in mammalian cell function [1][2][3][4], as an enzymatic cofactor [5], regulator of cellular ion channels [6][7][8] and energy metabolism [9]. Conditions such as Type 2 Diabetes [10][11][12], Alzheimer's [13,14] and cardiovascular disease [15,16] have been linked with magnesium deficiency, however the mechanisms of Mg 2+ regulation in such disease states are poorly understood [17,18].…”

Magnesium in the Central Nervous System

“…Experimental evidence indicates that intra--cellular Mg 2+ can modulate the activity and selectivity of these channels therefore affecting monovalent cation permeability. While an effect of intracellular Mg 2+ on CRAC channels cannot be completely excluded, a report by Prakriya and Lewis (2002) (Shi et al, 2002). The inhibitory effect of Mg 2+ is not restricted to cell membrane channels.…”

“…Recent studies have revealed that these two types of cell death exist following exposure to intense noise and that apoptosis appears extremely rapidly after the noise stress. Apoptosis has been shown to be the primary cell death pathway in the first day following noise exposure (Hu et al, 2002;. Contrary to birds or reptiles, a mammal's auditory hair cells do not regenerate if they are destroyed.…”