BK Channel Gating Mechanisms: Progresses Toward a Better Understanding of Variants Linked Neurological Diseases

Figures

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  FIGURE 1. Independent voltage and Ca2+ activation of BK channels. (A) Current traces activated by voltage pulses in low Ca2+ concentration (≤0.5 nM) without binding to Ca2+. (B) Steady state conductance of the channels (measured at the end of the current traces in panel (A)) at different voltages. The GV relation reflects voltage dependence of open probability of the channels. (C) Open probability of BK channels at different voltage and Ca2+ concentrations. At negative voltages (V < −100 mV) channels open in response to Ca2+ concentration changes without dependence on voltage sensor activation. (D) Dependence of open probability at −140 mV on Ca2+ concentration. The same results have been published previously (Yang et al., 2010).

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  FIGURE 2. Allosteric activation mechanism and structure of BK channels. (A) The allosteric model of BK channel activation. The channel undergoes an intrinsic closed-open transition (C and O), which is regulated by voltage sensor activation (R to A) and Ca2+ binding (X to X:Ca2+) with allosteric mechanisms. i.e., with each voltage sensor activation the channel open state is favored by an allosteric factor D; and with each Ca2+ binding to the channel the channel open state is favored by an allosteric factor C. L, J, and K are equilibrium constants for the respective transitions. Although voltage and Ca2+ can activate the channel independently, voltage sensor activation and Ca2+ binding affect each other with an allosteric factor E. In this model only 4 Ca2+ binding sites are assumed. Similar models containing 8 Ca2+ binding sites can also fit the electrophysiology data (Savalli et al., 2012). (B) BK channel structure with four Slo1 subunits (PDB entry: 6V38). Only two subunits are shown for the membrane spanning part of the channel. VSD: voltage sensing domain, PGD: pore-gate domain, CTD: cytosolic domain. (C) A single Slo1 subunit (PDB entry: 6V38). S0–S6: transmembrane segments, SF:…

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  FIGURE 3. BK mutations alter activation and link to neurological diseases. (A) The GOF (blue) and LOF (red) mutations mapped onto Slo1 structure. Yellow circles: Ca2+ ions bound to the channel. (B) The GOF mutation D434G and N536H in human Slo1 corresponds to D369G and N471H in mouse Slo1, respectively. Both mutations enhance currents at the same voltage and Ca2+ concentration. The current trace at +40 mV, which is most relevant physiological membrane potential, is highlighted in a thicker line. (C) Ca2+ dependence of the V1/2 of GV relations (the voltage where GV relation is half maximum, which is used to measure the voltage range in which the channel activates). The result shows that with the D369G and N471H mutations GV shifts to more negative voltages at all Ca2+ concentrations. The * shows that 1 μM Ca2+ concentration is most physiologically relevant. The same results have been published previously (Yang et al., 2010; Zhang et al., 2020).