Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

Liin, Sara I.; Larsson, Johan; Barro-Soria, René; Bentzen, Bo Hjorth; Larsson, H. Peter

doi:10.7554/elife.20272

Cited by 34 publications

(56 citation statements)

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“…We recently described that analogs of polyunsaturated fatty acids (PUFAs) are I Ks channel activators (Liin et al, 2015b, 2016). For example, the PUFA analog N-arachidonoyl taurine (N-AT) (Figure 1B) enhances the activity of the wild-type and mutated Kv7.1+KCNE1 channels and prevents arrhythmic beating in embryonic rat cardiomyocytes (Liin et al, 2015b, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…For example, the PUFA analog N-arachidonoyl taurine (N-AT) (Figure 1B) enhances the activity of the wild-type and mutated Kv7.1+KCNE1 channels and prevents arrhythmic beating in embryonic rat cardiomyocytes (Liin et al, 2015b, 2016). N-AT and other negatively charged PUFA analogs activate K V 7.1 and K V 7.1+KCNE1 channels by shifting the voltage of half-maximal activation ( V 50 ) toward more negative voltages (Liin et al, 2015b).…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1

et al. 2018

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In Brief Polyunsaturated fatty acid (PUFA) analogs are potentially anti-arrhythmic compounds, and understanding their functional mechanisms can aid in rational drug design. Liin et al. find that negatively charged PUFA analogs activate the cardiac potassium channel KV7.1 by dual independent mechanisms, demonstrating augmentation of channel activity through electrostatic interactions with both the pore and voltage-sensing domains of KV7.1.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1

et al. 2018

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“…More recently, the opening of KV channels has emerged as an alternative means to reducing cellular excitability and/or to controlling the duration of repolarization (Humphries and Dart, 2015;Liin et al, 2016a;Peretz et al, 2005Peretz et al, , 2007Tigerholm et al, 2012;Wulff et al, 2009;Xiong et al, 2008), since only small changes in the voltage dependence of activation of KV channels would be needed to reduce cellular excitability ( Figure 4). However, considering the clinical impact that KV channel modulators could have, due the diversity of KV channels and their defined tissue distribution, KV channels remain relatively unexploited as drug targets.…”

Section: Voltage-gated Ion Channels As Pharmacological Targetsmentioning

confidence: 99%

“…PUFAs open the WT and 3R Shaker KV channel (Börjesson and Elinder, 2011;Börjesson et al, , 2010Elinder and Liin, 2017;Ottosson et al, 2014;Xu et al, 2008), and the human KV7.1 and KV7.2/7.3 channel (Liin et al, 2015(Liin et al, , 2016a(Liin et al, , 2016b, via an electrostatic mechanism of action, exerted on the positively charged voltage sensor S4 ( Figure 5B). The negatively charged carboxyl group facilitate the outward movement of the voltage sensor, in the final opening step, and as consequence the KV channels open at more negative membrane potentials ( Figure 5C) (Börjesson et al, , 2010Liin et al, 2015Liin et al, , 2016b.…”

Section: Polyunsaturated Fatty Acidsmentioning

confidence: 99%

Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels

Ejneby¹

2018

Linköping University Medical Dissertations

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“…2B, compare red and black triangles). Because the mutation F351A separates the fluorescence change (due to S4 movement) from the ionic current change (due to movement of the gate) in both time and voltage (30,31,33), F351A makes it easier to distinguish effects of the different KCNE β-subunits on the S4 movement and/or the gate. We have previously shown (27) that KCNE3 does not modify the G(V) relation of KCNQ1-F351A (Fig.…”

Section: Kcne1mentioning

confidence: 99%

KCNE1 and KCNE3 Modulate KCNQ1 Channels by Affecting Different Gating Transitions

Barro-Soria

Ramentol

Liin

et al. 2017

Biophysical Journal

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KCNE β-subunits assemble with and modulate the properties of voltage-gated K + channels. In the heart, KCNE1 associates with the α-subunit KCNQ1 to generate the slowly activating, voltagedependent potassium current (I Ks ) in the heart that controls the repolarization phase of cardiac action potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K + channels that are voltageindependent K + channels in the physiological voltage range and important for controlling water and salt secretion and absorption. How KCNE1 and KCNE3 subunits modify KCNQ1 channel gating so differently is largely unknown. Here, we use voltage clamp fluorometry to determine how KCNE1 and KCNE3 affect the voltage sensor and the gate of KCNQ1. By separating S4 movement and gate opening by mutations or phosphatidylinositol 4,5-bisphosphate depletion, we show that KCNE1 affects both the S4 movement and the gate, whereas KCNE3 affects the S4 movement and only affects the gate in KCNQ1 if an intact S4-to-gate coupling is present. Further, we show that a triple mutation in the middle of the transmembrane (TM) segment of KCNE3 introduces KCNE1-like effects on the second S4 movement and the gate. In addition, we show that differences in two residues at the external end of the KCNE TM segments underlie differences in the effects of the different KCNEs on the first S4 movement and the voltage sensor-togate coupling.+ (Kv) channels are mainly expressed in excitable cells, where changes in the voltage across the membrane, such as action potentials, demand rapid channel activation and deactivation. Among Kv channels, the KCNQ1 channel (also called Kv7.1 or KvLQT1) differs from most other Kv channels in that KCNQ1 plays key physiological roles in nonexcitable cells, such as in epithelia, in addition to its roles in excitable cells, such as cardiomyocytes. The KCNQ1 channels display dramatically different biophysical properties in various cell types, differences that are thought to be mainly due to the KCNQ1 channel's ability to associate with five tissue-specific KCNE β-subunits to form different K + channel complexes (1-7). KCNQ1 subunits expressed by themselves form voltage-dependent K + channels that open at negative voltages (1, 2) ( Fig. 1 A and D, black squares). However, coassembly of KCNQ1 with KCNE1 (also called MinK) produces a much slower activating potassium current (I Ks ) in the heart that activates at positive voltages ( Fig. 1 B and D, black triangles) and shapes the repolarization phase of cardiac action potentials (1, 2). Mutations in the KCNQ1/KCNE1 complex are linked to life-threatening cardiac arrhythmias, such as torsade de pointes (8, 9). Association of KCNQ1 with KCNE3 (also called MiRP2) produces channels that are voltage-independent in the physiological voltage range (Fig. 1 C and D, black circles) and that are crucial in regulating the transport of water and salt in several epithelial tissues, including the colon, small intestine, and airways (3, 10, 11). Therefore, t...

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Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

Cited by 34 publications

References 60 publications

Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1

Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1

Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels

KCNE1 and KCNE3 Modulate KCNQ1 Channels by Affecting Different Gating Transitions

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