Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues.
Bohannon BM
,
Jowais JJ
,
Nyberg L
,
Olivier-Meo V
,
Corradi V
,
Tieleman DP
,
Liin SI
,
Larsson HP
.
???displayArticle.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.
Abramochkin,
Transcripts of Kv7.1 and MinK channels and slow delayed rectifier K+ current (IKs) are expressed in zebrafish (Danio rerio) heart.
2018, Pubmed
Abramochkin,
Transcripts of Kv7.1 and MinK channels and slow delayed rectifier K+ current (IKs) are expressed in zebrafish (Danio rerio) heart.
2018,
Pubmed
Barhanin,
K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current.
1996,
Pubmed
,
Xenbase
Bohannon,
ω-6 and ω-9 polyunsaturated fatty acids with double bonds near the carboxyl head have the highest affinity and largest effects on the cardiac IKs potassium channel.
2019,
Pubmed
,
Xenbase
Bohannon,
Polyunsaturated fatty acids produce a range of activators for heterogeneous IKs channel dysfunction.
2020,
Pubmed
,
Xenbase
Broomand,
Molecular movement of the voltage sensor in a K channel.
2003,
Pubmed
,
Xenbase
Börjesson,
Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids.
2008,
Pubmed
,
Xenbase
Börjesson,
An electrostatic potassium channel opener targeting the final voltage sensor transition.
2011,
Pubmed
,
Xenbase
Dougherty,
Cation-pi interactions involving aromatic amino acids.
2007,
Pubmed
Elinder,
Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels.
2017,
Pubmed
Fernández-Falgueras,
Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances.
2017,
Pubmed
Infield,
Cation-π Interactions and their Functional Roles in Membrane Proteins.
2021,
Pubmed
Jump,
The biochemistry of n-3 polyunsaturated fatty acids.
2002,
Pubmed
Kalstrup,
S4-S5 linker movement during activation and inactivation in voltage-gated K+ channels.
2018,
Pubmed
,
Xenbase
Larsson,
Polyunsaturated Fatty Acids as Modulators of KV7 Channels.
2020,
Pubmed
Liin,
Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel.
2015,
Pubmed
,
Xenbase
Liin,
Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations.
2016,
Pubmed
,
Xenbase
Liin,
Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1.
2018,
Pubmed
,
Xenbase
Moreno,
Effects of n-3 Polyunsaturated Fatty Acids on Cardiac Ion Channels.
2012,
Pubmed
Moreno,
Marine n-3 PUFAs modulate IKs gating, channel expression, and location in membrane microdomains.
2015,
Pubmed
Nerbonne,
Molecular physiology of cardiac repolarization.
2005,
Pubmed
Panaghie,
The role of S4 charges in voltage-dependent and voltage-independent KCNQ1 potassium channel complexes.
2007,
Pubmed
,
Xenbase
Pless,
Asymmetric functional contributions of acidic and aromatic side chains in sodium channel voltage-sensor domains.
2014,
Pubmed
,
Xenbase
Roden,
Clinical practice. Long-QT syndrome.
2008,
Pubmed
Sun,
Regulation of Voltage-Activated K(+) Channel Gating by Transmembrane β Subunits.
2012,
Pubmed
Sun,
Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.
2017,
Pubmed
,
Xenbase
Waddell-Smith,
Update on the Diagnosis and Management of Familial Long QT Syndrome.
2016,
Pubmed
Wang,
MinK-KvLQT1 fusion proteins, evidence for multiple stoichiometries of the assembled IsK channel.
1998,
Pubmed
Watanabe,
[Long QT syndrome].
2005,
Pubmed
Wu,
KCNE1 remodels the voltage sensor of Kv7.1 to modulate channel function.
2010,
Pubmed
,
Xenbase
Yang,
Single-channel properties of IKs potassium channels.
1998,
Pubmed
,
Xenbase
Yazdi,
Identification of PUFA interaction sites on the cardiac potassium channel KCNQ1.
2021,
Pubmed
,
Xenbase
