Polyunsaturated Fatty Acid Analogues Research Articles

Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues.

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.

Human-induced pluripotent stem cell-derived cardiomyocytes to study PUFA analogues as a potential treatment of long QT syndrome.

Long QT syndrome (LQTS) is an inheritable ventricular arrhythmia that predisposes patients to torsades de pointes and sudden cardiac death. Mutations in voltage-gated ion channels (VGC) and their regulatory β subunits involved in the cardiac action potential (AP) generate LQTS by prolonging the QT interval of the electrocardiogram. 15 types of LQTS has been described depending on the underlying gene mutated. LQT1 and LQT5 are described as loss-of-function mutations in genes that encode Kv7.1 (alpha pore-forming subunit) and its β-regulatory subunit KCNE1, respectively. Kv7.1/KCNE1 channels elicit one of the main repolarization currents (IKs) involved in the cardiac AP. Therefore, Kv7.1/KCNE1 channel-specific activators might be a potential treatment for LQTS. Polyunsaturated fatty acid (PUFA) analogues can broadly modulate cardiac VGC when applied on isolated channels in a heterologous system. In the present study, we measured the effects of these four compounds, Linoleoyl-taurine (LIN-Tau), docosahexaenoyl-Tau (DHA-Tau), Linoleoyl-Glycine (LIN-Gly), and DHA-Gly, on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). DHA-analogues shortened the hiPSC-CMs AP duration (APD), while LIN-analogues prolonged hiPSC-CMs APD. DHA-analogues were also tested in isogenic hiPSC-CMs lines for two KCNQ1 (Kv7.1 gene) mutations that cause LQT1, R190Q, and G269S. R190Q is an autosomal dominant missense mutation characterized by a 70-80 % reduction of IKs because of a dominant negative traffic defect. Moreover, we also analyzed DHA-analogues in a heterozygous missense KCNQ1 mutation, G269S. G269S mutation shows a net effect of less than 50% reduction of IKs current (haploinsufficiency). We here use a combination of hiPSC-CM monolayers with a high-resolution, all-optical electrophysiology system for screening the anti-arrhythmic properties of diverse PUFA analogues. Moreover, the well-characterized hiPSC-CMs mutants show us whether PUFA analogues might be a potential treatment approach for more than one type of LQT1.

Commonly Available Deep-Water Shrimps from the Arabian Sea along the Southwest Coast of Peninsular India as Prospective Nutritional Source

ABSTRACT Deep-water shrimps are non-conventional culinary delicacies due to the presence of essential nutrients, although they are predominantly unexplored marine fishery resources. The nutritional composition of deep-water shrimp species Aristeus alcocki, Heterocarpus chani, Plesionika quasigrandis, Solenocera choprai, and Metapenaeopsis andamanensis captured from Arabian Sea (southwest coast of peninsular India) was determined. The shrimp demonstrated a well-composed essential/non-essential amino acids ratio (0.76-0.84). Among other deep-water shrimps, protein content, total aromatic, and sulfur-enclosing amino acids were substantially higher in A. alcocki (12.69 g 100 g-1, 344 and 270 mg 100 g-1 wet tissue, respectively). The C20-22n-3 polyunsaturated fatty acid analogues (docosahexaenoic and eicosapentaenoic acid) were found to be in appreciable quantities (82-130 and 56-120 mg 100 g-1 wet edible portion, respectively) in the studied deep-water shrimp species. Lower thrombogenicity and atherogenicity indices (0.16-0.32 and 0.35-0.53, respectively) acknowledged the studied deep-water shrimp species as valuable health food items for cardioprotection and anti-platelet aggregation.

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

The cardiac ventricular action potential depends on several voltage-gated ion channels, including NaV, CaV, and KV channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (NaV, CaV, and KV). In addition, a PUFA analogue selective for the cardiac IKs channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.

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

The cardiac ventricular action potential depends on several voltage-gated ion channels, including NaV, CaV, and KV channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (NaV, CaV, and KV). In addition, a PUFA analogue selective for the cardiac IKs channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.

Polyunsaturated fatty acids produce a range of activators for heterogeneous IKs channel dysfunction.

Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium IKs channel. Disruption of the IKs current leads to the most common form of congenital long QT syndrome (LQTS), a disease that predisposes patients to ventricular arrhythmias and sudden cardiac death. We previously demonstrated that polyunsaturated fatty acid (PUFA) analogues increase outward K+ current in wild type and LQTS-causing mutant IKs channels. Our group has also demonstrated the necessity of a negatively charged PUFA head group for potent activation of the IKs channel through electrostatic interactions with the voltage-sensing and pore domains. Here, we test whether the efficacy of the PUFAs can be tuned by the presence of different functional groups in the PUFA head, thereby altering the electrostatic interactions of the PUFA head group with the voltage sensor or the pore. We show that PUFA analogues with taurine and cysteic head groups produced the most potent activation of IKs channels, largely by shifting the voltage dependence of activation. In comparison, the effect on voltage dependence of PUFA analogues with glycine and aspartate head groups was half that of the taurine and cysteic head groups, whereas the effect on maximal conductance was similar. Increasing the number of potentially negatively charged moieties did not enhance the effects of the PUFA on the IKs channel. Our results show that one can tune the efficacy of PUFAs on IKs channels by altering the pKa of the PUFA head group. Different PUFAs with different efficacy on IKs channels could be developed into more personalized treatments for LQTS patients with a varying degree of IKs channel dysfunction.

Differential Sensitivity of Cardiac Ion Channels to Polyunsaturated Fatty Acid Analogues

Differential Sensitivity of Cardiac Ion Channels to Polyunsaturated Fatty Acid Analogues

Molecular Mechanism of Polyunsaturated Fatty Acid Analogues as KV7.1-Channel Modulators

Negatively charged analogues of polyunsaturated fatty acids (PUFAs) have been shown to activate the human KV7.1+KCNE1 channel, which generates the repolarizing cardiac IKs current. Specific PUFA analogues activate both wild type KV7.1+KCNE1 and KV7.1+KCNE1 containing Long QT syndrome-associated mutations. Therefore, PUFA analogues represent a new class of KV7.1+KCNE1 channel activators that may aid in development of novel anti-arrhythmic drugs. To determine the molecular mechanism of how PUFA analogues activate KV7.1+KCNE1, we here combine electrophysiology recordings and site-directed mutagenesis with a panel of PUFA analogues with distinct properties. We identify two main effects of PUFA analogues on KV7.1 that are dependent on discrete channel motifs. The first effect is a shift in the voltage dependence of channel opening that is critically dependent on specific S4 arginines in the voltage sensor domain of KV7.1. Intriguingly, different S4 arginines are important in KV7.1 and KV7.1+KCNE1. The second effect is alteration in the maximum conductance that is critically dependent on the S6 residue K326 in the pore domain of KV7.1. Both effects appear to be primarily electrostatic. Our findings provide novel insights into how KV7.1+KCNE1 channel activators, such as PUFA analogues, simultaneously may interact with the voltage sensor domain and the pore domain to alter channel activity. Our findings also contribute pharmacological support to the hypothesis that KV7.1 and KV7.1+KCNE1 open from different conformational states.

Polyunsaturated Fatty Acid Analogues Act Anti-Arrhythmic on the Cardiac IKs Channel

Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the β-subunit KCNE1 form the cardiac IKs channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as IKs channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Charged n-3 and n-6 PUFAs affect the voltage dependence of Kv7.1 by shifting the conductance versus voltage curve towards more negative voltages. In contrast, uncharged methyl esters of the PUFAs do not affect the voltage dependence of Kv7.1. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open Kv7.1. The PUFA effect is pH dependent. This is likely because high pH deprotonates the PUFA, making a larger fraction of PUFA molecules negatively charged and thereby able to affect Kv7.1 channel voltage dependence. We further show that KCNE1 co-expression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogues with a decreased pKa value, to preserve their negative charge at neutral pH, restore the sensitivity to open IKs channels. PUFA analogues with a positively charged head group inhibit IKs channels. These different PUFA analogues could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that a PUFA analogue with a permanently negatively charged head group acts anti-arrhythmic in cardiomyocytes. This permanently negatively charged PUFA analogue induces a shortening of action potential duration in embryonic rat cardiomyocytes and restores rhythmic beating in an arrhythmia model.

Tumor cell mitochondrial matrix/cristae complexes as potential sites for anticancer therapy with polyunsaturated fatty acid analogues

The consequences of incubating human cancer cells with ETYA, a competitive analogue of arachidonic acid, and the reported responses of cells cultured with polyunsaturated fatty acids indicate that polyunsaturated fatty acid analogues or their modified congeners could represent potential cytotoxic anticancer agents. The inner mitochrondrial membrane and matrix may represent important targets for such agents, since they seem unusually susceptible to ETYA-induced oxidative stress.