Key result
PKCε inhibitory peptidomimmetics decreased PKC-induced hERG τ activation by 80% and half-maximum activation voltage by 90% at steady state.
Specific PKC isoforms, particularly PKCε, play distinct roles in modulating the biophysical properties of the hERG channel, which may have implications for understanding cardiac repolarization.
May guide isoform-selective PKC inhibitor development; hypothesis-generating in animal models and leaves open human translation.
Protein kinases C (PKC) modulate the activity of the Kv11.1 ion channel current (hERG). However, the differential effects of specific PKC subtypes on the biophysics of the channel are unknown. The pharmaceutical tools to selectively modulate PKC subtypes are not membrane permeable and must be added directly to the intracellular solution in electrophysiology studies. Here, the PatchXpress electrophysiology robot was used to voltage clamp up to 16 cells simultaneously yet asynchronously across individual Sealchip chambers. The precision afforded by repeats of automation procedures minimized the experimental errors typical of these assays. Eight well-known PKC selective peptidomimmetics and general synthetic modulators were used to modulate the protein-protein interactions between hERG and the major PKC subtypes. We identified a specific role for the PKCε inhibitory peptidomimmetics in decreasing PKC-induced hERG τ activation (80%) and half-maximum activation voltage (90%) at steady state; a specific PKCε activator exhibited the opposite effect. Disruption of PKCβ, PKCα, and PKCη interactions also showed significant effects albeit of lower magnitudes. The effect of PKCδ inhibitor was only marginal. A significant correlation was observed between the shifts in τ activation and half-maximum voltage at steady state (R(2)= 0.85). Peak current amplitudes and time constant of deactivation remained unaffected in all conditions.
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Radresa et al. (2014) studied this question. PKC selective peptidomimmetics and general synthetic modulators was evaluated on hERG τ activation and half-maximum activation voltage at steady state. PKCε inhibitory peptidomimmetics decreased PKC-induced hERG τ activation by 80% and half-maximum activation voltage by 90% at steady state.
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