Abstract
In Shaker K+ channels, the S4-S5 linker couples the voltage sensor (VSD) and pore domain (PD). Another coupling mechanism is revealed using two W434F-containing channels: L361R:W434F and L366H:W434F. In L361R:W434F, W434F affects the L361R VSD seen as a shallower charge-voltage (Q-V) curve that crosses the conductance-voltage (G-V) curve. In L366H:W434F, L366H relieves the W434F effect converting a non-conductive channel in a conductive one. We report a chain of residues connecting the VSD (S4) to the selectivity filter (SF) in the PD of an adjacent subunit as the molecular basis for voltage sensor selectivity filter gate (VS-SF) coupling. Single alanine substitutions in this region (L409A, S411A, S412A, or F433A) are enough to disrupt the VS-SF coupling, shown by the absence of Q-V and G-V crossing in L361R:W434F mutant and by the lack of ionic conduction in the L366H:W434F mutant. This residue chain defines a new coupling between the VSD and the PD in voltage-gated channels.
Highlights
Voltage-gated ion channels play fundamental roles in many physiological processes, such as generating the nerve impulse and regulating neuronal excitability, shaping the pacemaker in the heart, or controlling muscular contractility
All alanine substitutions on L366H:W434F channels were sufficient to decrease the K+ conduction to levels comparable to the W434F phenotype. This indicates that the VS-selectivity filter (SF) coupling has been disrupted. These results demonstrate that the voltage sensor selectivity filter gate (VS-SF) coupling (1) comprises the proposed chain of residues, in domain-swapped channels; (2) is dependent on the volume of these residues; and (3) reveals that the voltage sensor domain (VSD) affects the dynamics of the SF gate and that the SF gate affects the movement of the VSD
We found that Q-V and G-V curves do not cross each other when any of the alanine substitutions are performed in the presence of the W434F mutation (Figure 2A-F, Table 1)
Summary
Voltage-gated ion channels play fundamental roles in many physiological processes, such as generating the nerve impulse and regulating neuronal excitability, shaping the pacemaker in the heart, or controlling muscular contractility. Voltage-gated potassium channels (KV) are members of the voltage-gated ion channels superfamily, responsible for the repolarization phase of the action potential, for maximal action potential firing frequency and for keeping the membrane potential negative in non-excitable cells. In domain-swapped channels, the VSD from one subunit is in close contact with the PD from a neighboring subunit, forming an extensive inter-subunit non-covalent interface. In non-domain-swapped channels, the VSD and the PD from the same subunit forms a similar non-covalent interface and the domains are connected by a shorter version of the S4-S5 linker
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