Kv11.1 protein localizes in cholesterol and sphingolipid enriched membranes, and membrane cholesterol depletion or loading modulates the activation and deactivation kinetics of the Kv11.1 current.
Does membrane cholesterol modulate the function and localization of Kv11.1 (hERG1) potassium channels?
Kv11.1 (hERG) channels localize to cholesterol-enriched membrane microdomains, and membrane cholesterol levels directly modulate their electrophysiological properties, which may impact cardiac repolarization.
The localization of ion channels to specific membrane microdomains can impact the functional properties of channels and their role in cellular physiology. We determined the membrane localization of human Kv11.1 (hERG1) alpha-subunit protein, which underlies the rapidly activating, delayed rectifier K(+) current (I(Kr)) in the heart. Immunocytochemistry and membrane fractionation using discontinuous sucrose density gradients of adult canine ventricular tissue showed that Kv11.1 channel protein localized to both the cell surface and T-tubular sarcolemma. Furthermore, density gradient membrane fractionation using detergent (Triton X-100) and non-detergent (OptiPrep) methods from canine ventricular myocytes or HEK293 cells demonstrated that Kv11.1 protein, along with MiRP1 and Kv7.1 (KCNQ1) proteins, localize in cholesterol and sphingolipid enriched membrane fractions. In HEK293 cells, Kv11.1 channels, but not long QT-associated mutant G601S-Kv11.1 channels, also localized to cholesterol and sphingolipid enriched membrane fractions. Depletion of membrane cholesterol from HEK293 cells expressing Kv11.1 channels using methyl-beta-cyclodextrin (MbetaCD) caused a positive shift of the voltage dependence of activation and an acceleration of deactivation kinetics of Kv11.1 current (I(Kv11.1)). Cholesterol loading of HEK293 cells reduced the steep voltage dependence of I(Kv11.1) activation and accelerated the inactivation kinetics of I(Kv11.1). Incubation of neonatal mouse myocytes in MbetaCD also accelerated the deactivation kinetics of I(Kr). We conclude that Kv11.1 protein localizes in cholesterol and sphingolipid enriched membranes and that membrane cholesterol can modulate I(Kv11.1) and I(Kr).
Balijepalli et al. (Mon,) reported a other. Membrane cholesterol modulation was evaluated on Voltage dependence of activation and deactivation kinetics of Kv11.1 current. Kv11.1 protein localizes in cholesterol and sphingolipid enriched membranes, and membrane cholesterol depletion or loading modulates the activation and deactivation kinetics of the Kv11.1 current.
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