Cloning and functional characterization of the smooth muscle ether-a-go-go-related gene K+ channel -: Potential role of a conserved amino acid substitution in the S4 region

The human ether-a-go-go-related gene (HERG) product forms the pore-forming subunit of the delayed rectifier K+ channel in the heart. Unlike the cardiac isoform, the erg K+ channels in native smooth muscle demonstrate gating properties consistent with a role in maintaining resting potential. We have cloned the smooth muscle isoform of HERG, denoted as erg1-sm, from human and rabbit colon. erg1-sm is truncated by 101 amino acids in the C terminus due to a single nucleotide deletion in the 14th exon. Sequence alignment against HERG showed a substitution of alanine for valine in the S4 domain. When expressed in Xenopus oocytes, erg1-sm currents had much faster activation and deactivation kinetics compared with HERG. Step depolarization positive to -20 mV consistently produced a transient outward component. The threshold for activation of erg1-sm was -60 mV and steady-state conductance was similar to10-fold greater than HERG near the resting potential of smooth muscle. Site-directed mutagenesis of alanine to valine in the S4 region of erg1-sm converted many of the properties to that of the cardiac HERG, including shifts in the voltage dependence of activation and slowing of deactivation. These studies define the functional role of a novel isoform of the ether-a-go-go-related gene K+ channel in smooth muscle.