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

Voltage-gated potassium (K_V) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K_Vchannel 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 K_Vchannel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K_Vchannel 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 I_Kschannel - a tetrameric potassium channel complex formed by K_V7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I_Kschannel 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 I_Kschannel 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 I_Kschannel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.