Key result
PUFA analogues with taurine and cysteic head groups produced the most potent activation of IKs channels by shifting the voltage dependence of activation.
Why the study?
It was unknown whether the efficacy of polyunsaturated fatty acids could be tuned by different functional head groups altering electrostatic interactions with IKs channels.
The efficacy of PUFAs on IKs channels can be tuned by altering the pKa of the PUFA head group, suggesting potential for personalized treatments in LQTS.
May offer a novel IKs-targeted approach in LQTS; leaves open clinical translation from cellular data.
Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium IKs channel. Disruption of the IKs current leads to the most common form of congenital long QT syndrome (LQTS), a disease that predisposes patients to ventricular arrhythmias and sudden cardiac death. We previously demonstrated that polyunsaturated fatty acid (PUFA) analogues increase outward K+ current in wild type and LQTS-causing mutant IKs channels. Our group has also demonstrated the necessity of a negatively charged PUFA head group for potent activation of the IKs channel through electrostatic interactions with the voltage-sensing and pore domains. Here, we test whether the efficacy of the PUFAs can be tuned by the presence of different functional groups in the PUFA head, thereby altering the electrostatic interactions of the PUFA head group with the voltage sensor or the pore. We show that PUFA analogues with taurine and cysteic head groups produced the most potent activation of IKs channels, largely by shifting the voltage dependence of activation. In comparison, the effect on voltage dependence of PUFA analogues with glycine and aspartate head groups was half that of the taurine and cysteic head groups, whereas the effect on maximal conductance was similar. Increasing the number of potentially negatively charged moieties did not enhance the effects of the PUFA on the IKs channel. Our results show that one can tune the efficacy of PUFAs on IKs channels by altering the pKa of the PUFA head group. Different PUFAs with different efficacy on IKs channels could be developed into more personalized treatments for LQTS patients with a varying degree of IKs channel dysfunction.
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Bohannon et al. (2019) studied Long QT syndrome (LQTS) / IKs channel dysfunction. Polyunsaturated fatty acid (PUFA) analogues was evaluated on Activation of IKs channels (voltage dependence and maximal conductance). PUFA analogues with taurine and cysteic head groups produced the most potent activation of IKs channels by shifting the voltage dependence of activation.
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