Abstract
MinK has neither the P region nor signature sequence that characterizes pore-forming subunits of all known K+ channels. A specific minK region has now been identified that affects external blockade by 2 common probes of K+ channel pores. When mutated to cysteine, residues in this region render minK susceptible to covalent blockade by methanethiosulfonate ethylsulfonate and alter reversible inhibition by tetraethylammonium. The 2 blockers are found to share overlapping binding site determinants and to interact. Since inhibition by external tetraethylammonium is sensitive to voltage and to the internal concentration of permeant ions, we argue that tetraethylammonium blocks by occluding the external end of a water-filled transmembrane pore. These findings support the view that minK is directly involved in forming a K+-selective ion conduction pathway.
Highlights
The pore of an ion channel determines its selectivity and conduction characteristics, and residues that line channel pores have been sought to study the molecular basis for channel function (Hille, 1992)
MTSEA irreversibly blocks both wild-type minK and cysteine-free C107A-minK in which the single native cysteine in minK is mutated to alanine; this appears to result from modification of the cysteine in a non-minK protein that is critical for minK channel function (Tai et al, 1996)
To identify residues that might contribute to a channel pore, minK positions 42–55 were mutated individually to cysteine in the otherwise cysteine-free C107A protein
Summary
The pore of an ion channel determines its selectivity and conduction characteristics, and residues that line channel pores have been sought to study the molecular basis for channel function (Hille, 1992). One successful method has been to screen site-specific channel mutants for residues that alter blockade by agents that physically occlude the ion conduction pathway (Miller, 1995). MinK is found in the plasma membrane of cardiac and auditory cells where it appears to mediate a slowly activating, voltage-dependent, Kϩ-selective current (Folander et al, 1990; Honore et al, 1991; Sakagami et al, 1991; Freeman and Kass, 1993; Varnum et al, 1993; Marcus and Shen, 1994). MinK has just 130 amino acids and shows no homology with known Kϩ channels to suggest the molecular basis for its function
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