Mechanistic insights into robust cardiac I-Ks potassium channel activation by aromatic polyunsaturated fatty acid analogues

Nyberg, Leif (author): Linköpings universitet,Institutionen för biomedicinska och kliniska vetenskaper,Medicinska fakulteten,Univ Miami, FL 33136 USA

Liin, Sara (author): Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten

(creator_code:org_t)

Related links:: https://liu.diva-por... (primary) (Raw object); show more...; https://urn.kb.se/re...; https://doi.org/10.7...; show less...

Abstract Subject headings

Voltage-gated potassium (K-V) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K-V 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 K-V channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K-V 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 I-Ks channel - a tetrameric potassium channel complex formed by K(V)7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I-Ks 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 I-Ks 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 I-Ks channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.

By the author/editor: Bohannon, Briana ...; Jowais, Jessica ...; Nyberg, Leif; Olivier-Meo, Van ...; Corradi, Valenti ...; Tieleman, D. Pet ...; show more...; Liin, Sara; Larsson, H. Pete ...; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biophysics

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