Polyunsaturated fatty acid analogues differentially affect cardiac NaV, CaV, and KV channels through unique mechanisms

Bohannon, Briana M; Cruz, A.; Wu, X; Jowais, Jessica; Perez, Marta E.; Dykxhoorn, Derek M.; Liin, Sara I.; Larsson, H. Peter

doi:10.7554/elife.51453

Cited by 17 publications

(19 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Polyunsaturated fatty acids (PUFAs) affect many different ion channels, such as voltage-gated K + , Na + , and Ca 2+ channels, as well as ryanodine receptors ( Xiao et al, 2001 ; Hamilton et al, 2003 ; Oliver et al, 2004 ; Xiao et al, 2005 ; Ottosson et al, 2014 ; Farag et al, 2016 ; Tian et al, 2016 ; Liin et al, 2018 ; Bohannon et al, 2020 ). However, the molecular mechanisms behind the effects of PUFAs are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

Identification of PUFA interaction sites on the cardiac potassium channel KCNQ1

Nikesjö

Miranda

Corradi

et al. 2021

Journal of General Physiology

Self Cite

View full text Add to dashboard Cite

Polyunsaturated fatty acids (PUFAs), but not saturated fatty acids, modulate ion channels such as the cardiac KCNQ1 channel, although the mechanism is not completely understood. Using both simulations and experiments, we find that PUFAs interact directly with the KCNQ1 channel via two different binding sites: one at the voltage sensor and one at the pore. These two amphiphilic binding pockets stabilize the negatively charged PUFA head group by electrostatic interactions with R218, R221, and K316, while the hydrophobic PUFA tail is selectively stabilized by cassettes of hydrophobic residues. The rigid saturated tail of stearic acid prevents close contacts with KCNQ1. By contrast, the mobile tail of PUFA linoleic acid can be accommodated in the crevice of the hydrophobic cassette, a defining feature of PUFA selectivity in KCNQ1. In addition, we identify Y268 as a critical PUFA anchor point underlying fatty acid selectivity. Combined, this study provides molecular models of direct interactions between PUFAs and KCNQ1 and identifies selectivity mechanisms. Long term, this understanding may open new avenues for drug development based on PUFA mechanisms.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification of PUFA interaction sites on the cardiac potassium channel KCNQ1

Nikesjö

Miranda

Corradi

et al. 2021

Journal of General Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previously, various in vivo and in vitro studies showed that ω-3 PUFA could influence the electrophysiology of atrial and ventricular cardiomyocytes by alleviating their excitability, and cytosolic fluctuations of calcium, especially in damaged or ischemic cells that are prone to depolarization and arrhythmia [10]. Recently, in one study, the heart's electrical activity or Long QT Syndrome was described as mediated by the involvement of PUFAs [16]. PUFA analogues modulated the capacity of different voltage-gated ion channels (NaV, CaV, and KV).…”

Section: First Biological Mechanism Suggests That the Cellular Organelles And Membranes Are Controlled Through Their Lipidic Compositionmentioning

confidence: 99%

Essential Fatty Acids as Biomedicines in Cardiac Health

et al. 2021

View full text Add to dashboard Cite

The destructive impact of cardiovascular diseases on health, including heart failure, peripheral artery disease, atherosclerosis, stroke, and other cardiac pathological conditions, positions these health conditions as leading causes of increased global mortality rates, thereby impacting the human quality of life. The considerable changes in modern lifestyles, including the increase in food intake and the change in eating habits, will unavoidably lead to an unbalanced consumption of essential fatty acids, with a direct effect on cardiovascular health problems. In the last decade, essential fatty acids have become the main focus of scientific research in medical fields aiming to establish their impact for preventing cardiovascular diseases and the associated risk factors. Specifically, polyunsaturated fatty acids (PUFA), such as omega 3 fatty acids, and monounsaturated fatty acids from various sources are mentioned in the literature as having a cardio-protective role, due to various biological mechanisms that are still to be clarified. This review aims to describe the major biological mechanisms of how diets rich in essential fatty acids, or simply essential fatty acid administration, could have anti-inflammatory, vasodilatory, anti-arrhythmic, antithrombotic, antioxidant, and anti-atherogenic effects. This review describes findings originating from clinical studies in which dietary sources of FAs were tested for their role in mitigating the impact of heart disorders in human health.

show abstract

“… 165 Polyunsaturated fatty acids (PUFAs) and their analogs N‐arachidonoyl taurine have been found to speed up Kv7.1 channel opening and restore channel gating of many different mutant channels 226 PUFAs and their analogs are effective in shortening the cardiac action potential in pharmacologically prolonged ventricular action potential and QT interval in isolated guinea pig hearts 227 and in hIPSC‐CM. 228 Therefore, activators of Kv7.1 are also worth developing to treat LQT1 based on structure‐function studies on diverse IKs channel mutations. However, PUFAs analogs vary in selectivity and different effects for Kv7.1, Nav1.5, and Cav1.2 through nonidentical mechanisms.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

Chen

Wang

et al. 2021

Clinical & Translational Med

View full text Add to dashboard Cite

Cardiac voltage‐gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC‐related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life‐threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart‐related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well‐studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation.

show abstract

Polyunsaturated fatty acid analogues differentially affect cardiac NaV, CaV, and KV channels through unique mechanisms

Cited by 17 publications

References 64 publications

Identification of PUFA interaction sites on the cardiac potassium channel KCNQ1

Identification of PUFA interaction sites on the cardiac potassium channel KCNQ1

Essential Fatty Acids as Biomedicines in Cardiac Health

Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

Contact Info

Product

Resources

About