Key result
Two hydrogen bonds near the extracellular surface (Asp447-Trp434 and Tyr445-Thr439) act as molecular timers that regulate the entry of voltage-gated potassium channels into slow inactivation.
The study identifies specific intra- and inter-subunit hydrogen bonds that act as molecular timers controlling the rate of slow inactivation in voltage-gated potassium channels.
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May inform Kv channel modulator design for arrhythmias; leaves open validation in cardiac models.
Voltage-gated potassium (Kv) channels enable potassium efflux and membrane repolarization in excitable tissues. Many Kv channels undergo a progressive loss of ion conductance in the presence of a prolonged voltage stimulus, termed slow inactivation, but the atomic determinants that regulate the kinetics of this process remain obscure. Using a combination of synthetic amino acid analogs and concatenated channel subunits we establish two H-bonds near the extracellular surface of the channel that endow Kv channels with a mechanism to time the entry into slow inactivation: an intra-subunit H-bond between Asp447 and Trp434 and an inter-subunit H-bond connecting Tyr445 to Thr439. Breaking of either interaction triggers slow inactivation by means of a local disruption in the selectivity filter, while severing the Tyr445-Thr439 H-bond is likely to communicate this conformational change to the adjacent subunit(s). DOI: http://dx.doi.org/10.7554/eLife.01289.001.
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Pless et al. (2013) studied this question. Synthetic amino acid analogs and targeted mutations vs. Wild-type channels was evaluated on Rate of slow inactivation (inactivation time constant). Two hydrogen bonds near the extracellular surface (Asp447-Trp434 and Tyr445-Thr439) act as molecular timers that regulate the entry of voltage-gated potassium channels into slow inactivation.
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