Human
ether-à-go-go-related gene (HERG)
potassium channels play an important role in cardiac action potential repolarization, and HERG dysfunction can cause
cardiac arrhythmias. However, recent evidence suggests a role for HERG in the proliferation and progression of multiple types of
cancers, making it an attractive target for
cancer therapy.
Ceramide is an important second messenger of the
sphingolipid family, which due to its proapoptotic properties has shown promising results in animal models as an
anticancer agent. Yet the acute effects of
ceramide on HERG
potassium channels are not known. In the present study we examined the effects of cell-permeable
C(6)-ceramide on HERG
potassium channels stably expressed in HEK-293 cells.
C(6)-ceramide (10 microM) reversibly inhibited HERG channel current (I(HERG)) by 36 +/- 5%. Kinetically,
ceramide induced a significant hyperpolarizing shift in the current-voltage relationship (DeltaV(1/2) = -8 +/- 0.5 mV) and increased the deactivation rate (43 +/- 3% for tau(fast) and 51 +/- 3% for tau(slow)). Mechanistically,
ceramide recruited HERG channels within
caveolin-enriched
lipid rafts.
Cholesterol depletion and repletion experiments and mathematical modeling studies confirmed that inhibition and gating effects are mediated by separate mechanisms. The
ceramide-induced hyperpolarizing gating shift (raft mediated) could offset the impact of inhibition (raft independent) during cardiac action potential repolarization, so together they may nullify any negative impact on cardiac rhythm. Our results provide new insights into the effects of
C(6)-ceramide on HERG channels and suggest that
C(6)-ceramide can be a promising therapeutic for
cancers that overexpress HERG.