Mechanistic insights into robust cardiac I_Kspotassium channel activation by aromatic polyunsaturated fatty acid analogues

Abstract

Voltage-gated potassium (KV) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. KV channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore KV channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of KV channel activators with potential applications in the treatment of arrhythmogenic disorders such as Long QT Syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac IKs channel - a tetrameric potassium channel complex formed by KV7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac IKs channel and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the IKs channel by generating modified aromatic head groups designed to probe cation-pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the IKs channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.

PUFA stabilizes a conductive state of the selectivity filter in IKs channels

“…The result is a potent activation of IKs channels, with an increase of the maximum conductance by binding to Site II and a shift of the voltage dependence of activation of the channel by binding to Site I. The mechanism of the voltage shift effects at Site I, where the PUFA head group electrostatically interacts with positively charged S4 residues and thereby facilitates channel activation, has been investigated in previous studies 14, 27, 18, 28 . However, less is known about the molecular mechanism by which PUFA increases the maximum conductance (Gmax) of the channel following binding to Site II.…”