Hydrogen bonds as molecular timers for slow inactivation in voltage-gated potassium channels

TY - JOUR

T1 - Hydrogen bonds as molecular timers for slow inactivation in voltage-gated potassium channels

AU - Pless, Stephan Alexander

AU - Galpin, Jason D

AU - Niciforovic, Ana P

AU - Kurata, Harley T

AU - Ahern, Christopher A

PY - 2013/12/10

Y1 - 2013/12/10

N2 - 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).

AB - 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).

U2 - 10.7554/eLife.01289

DO - 10.7554/eLife.01289

M3 - Journal article

C2 - 24327560

SN - 2050-084X

VL - 2

SP - e01289

JO - eLife

JF - eLife

ER -