Abstract
Epigallocatechin-3-Gallate (EGCG) has been extensively studied for its protective effect against cardiovascular disorders. This effect has been attributed to its action on multiple molecular pathways and transmembrane proteins, including the cardiac Nav1.5 channels, which are inhibited in a dose-dependent manner. However, the molecular mechanism underlying this effect remains to be unveiled. To this aim, we have characterized the EGCG effect on Nav1.5 using electrophysiology and molecular dynamics (MD) simulations. EGCG superfusion induced a dose-dependent inhibition of Nav1.5 expressed in tsA201 cells, negatively shifted the steady-state inactivation curve, slowed the inactivation kinetics, and delayed the recovery from fast inactivation. However, EGCG had no effect on the voltage-dependence of activation and showed little use-dependent block on Nav1.5. Finally, MD simulations suggested that EGCG does not preferentially stay in the center of the bilayer, but that it spontaneously relocates to the membrane headgroup region. Moreover, no sign of spontaneous crossing from one leaflet to the other was observed, indicating a relatively large free energy barrier associated with EGCG transport across the membrane. These results indicate that EGCG may exert its biophysical effect via access to its binding site through the cell membrane or via a bilayer-mediated mechanism.
Highlights
Ion channels are pore-forming transmembrane proteins involved with the transport of ions through cell membranes
The pharmacological effects of EGCG (Figure 1a) on the cardiac sodium channel isoform were investigated using tsA201 cells transiently transfected with the human Nav 1.5 channel in the presence of its regulatory subunit Nav -β1
As previously reported by Kang et al [30], EGCG superfusion induced a dose-dependent inhibition of the Nav 1.5 channel
Summary
Ion channels are pore-forming transmembrane proteins involved with the transport of ions through cell membranes. Their activity is essential for the excitation-contraction coupling in cardiac cells. Within the nine isoforms of voltage-gated sodium channels, Nav 1.5 displays a preponderant expression in cardiac cells [1]. This isoform is composed of intracellular N and C terminal tails and four homologous domains (DI-DIV), each consists of six transmembrane segments (S1–S6). These domains fold together with their S5-S6 segments to build a highly selective Na+ pore [2,3]
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