Noncanonical mechanism of voltage sensor coupling to pore revealed by tandem dimers of Shaker

In voltage-gated potassium channels (VGKC), voltage sensors (VSD) endow voltage-sensitivity to pore domains (PDs) through a not fully understood mechanism. Shaker-like VGKC show domain-swapped configuration: VSD of one subunit is covalently connected to its PD by the protein backbone (far connection) and non-covalently to the PD of the next subunit (near connection). VSD-to-PD coupling is not fully explained by far connection only, therefore an additional mechanistic component may be based on near connection. Using tandem dimers of Shaker channels we show functional data distinguishing VSD-to-PD far from near connections. Near connections influence both voltage-dependence of C-type inactivation at the selectivity filter and overall PD open probability. We speculate a conserved residue in S5 (S412 in Shaker), within van der Waals distance from next subunit S4 residues is key for the noncanonical VSD-to-PD coupling. Natural mutations of S412-homologous residues in brain and heart VGKC are related to neurological and cardiac diseases.