Biology subjects

Liin, S. I.

Publications and source records attributed to Liin, S. I..

5 recordsLinked to original sources

bioRxiv2025

A broad set of synthetic cannabinoid receptor agonists inhibit the cardiac voltage-gated potassium channel hERG

Synthetic cannabinoid receptor agonists (SCRAs) is a large group of structurally diverse designer drugs (analogues of controlled substances) associated with intense and sometimes fatal intoxication. Cardiac symptoms including tachycardia and arrhythmia are common consequences of SCRA consumption. However, little is known about the mechanisms through which SCRAs may perturb cardiac rhythm. Here we used electrophysiological techniques to screen 36 SCRAs on two ion channels responsible for cardiomyocyte repolarization, hERG (also called KV11.1) and KV7.1/KCNE1. We report that the majority of tested SCRAs inhibited hERG, primarily by reducing channel conductance, and some also inhibited KV7.1/KCNE1. In silico data suggests that SCRAs use a known drug binding site in the pore of the hERG channel, shared by established hERG blockers like astemizole, where a planar SCRA molecule lays perpendicular to the ion conducting pathway. Experimental and in silico data identify SCRA structural features associated with prominent inhibitory effects on hERG, with chemical moieties allowing bond formation and/or the ability to fit into the vestibule being important. Structure-activity-relationships for SCRA effects on hERG, KV7.1/KCNE1 and the cannabinoid receptor 1 (CB1) varied, demonstrating the importance of assessing SCRA effects on multiple potential targets. In conclusion, we found SCRAs to be inhibitors of cardiac voltage-gated potassium channels important for cardiomyocyte repolarization. These results offer mechanistic insight into potentially detrimental SCRA effects on the heart and highlight the urgency of more extensive investigation of SCRAs on cardiac function.

pharmacology and toxicology↗

bioRxiv2025

Two-step voltage-sensor activation of the human KV7.4 channel and effect of a deafness-associated mutation

Voltage-gated, potassium-selective KV7.4 channels are expressed in the inner ear and are crucial for hair-cell function and survival. Loss-of-function variants of KCNQ4, the gene encoding KV7.4-channel subunits, cause non-syndromic progressive hearing loss (DFNA2). KV7.4 opening requires a voltage-dependent conformational change (activation) of the charged voltage-sensor domains (VSDs), and its transduction to the pore. Previously, fast charge displacement was reported during VSD activation at negative potentials, but it is unclear how this is coupled to slow channel opening occurring at more depolarized potentials. Here, we optically tracked KV7.4 VSD activation with voltage-clamp fluorometry, leveraging two different fluorophores and pulsed excitation, to thoroughly characterize VSD movements. We found that VSD activation comprises several voltage-dependent transitions, some of which had kinetics and voltage-dependence matching those of channel opening and closing. The deafness-associated mutation R216H, which substitutes a charged amino-acid in the VSD, impaired both VSD movements and channel opening, shifting them towards more depolarized potentials. This suggested that R216H impaired KV7.4 function by destabilizing VSD activation. Using molecular dynamics, we found that H216 reduced intramolecular interactions, thus decreasing the stability of an active VSD conformation. We propose that the KV7.4 VSD activates in two steps: a fast movement at negative voltages that represents a first transition to an intermediate state of activation; and this is followed by slower, depolarized component that represents subsequent full VSD activation, which drives channel opening.

biophysics↗

bioRxiv2023

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.

physiology↗

bioRxiv2021

Subtype specific responses in hKv7.4 and hKv7.5 channels to polyunsaturated fatty acids

The KV7.4 and KV7.5 subtypes of voltage-gated potassium channels are expressed in several tissues where they play a role in physiological processes such as sound amplification in the cochlea and adjusting vascular smooth muscle tone. Therefore, the mechanisms that regulate KV7.4 and KV7.5 channel function are of interest. Here, we study the effect of polyunsaturated fatty acids (PUFAs) on human KV7.4 and KV7.5 channels expressed in Xenopus oocytes. We report that KV7.5 is activated by PUFAs, which shift the V50 of the conductance versus voltage (G(V)) curve towards more negative voltages. This response depends on the charge of the head group as an uncharged PUFA analogue has no effect and a positively charged PUFA analogue induces positive V50 shifts. In contrast, we find that the KV7.4 channel is inhibited by PUFAs, which shift V50 towards more positive voltages. No effect on V50 of KV7.4 is observed by an uncharged or a positively charged PUFA analogue. Oocytes co-expressing KV7.4 and KV7.5 display an intermediate response to PUFAs. Altogether, the KV7.5 channels response to PUFAs is like that previously observed in KV7.1-7.3 channels, whereas the KV7.4 channel response is opposite, revealing subtype specific responses to PUFAs.

biophysics↗

bioRxiv2019

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 all three cardiac ion channels (NaV, CaL, and IKs). In addition, PUFA analogues do not modulate these channels through a shared mechanism. Our data suggest that different PUFA analogues could be tailored towards specific forms of LQTS, which are caused by mutations in distinct cardiac ion channels, and thus restore a normal ventricular action potential.

biophysics↗