Biology subjects

Hassinen, M.

Publications and source records attributed to Hassinen, M..

2 recordsLinked to original sources

bioRxiv2021

Effect of channel assembly (KCNQ1 or KCNQ1 + KCNE1) on the response of zebrafish IKs to IKs inhibitors and activators

In cardiac myocytes, the slow component of the delayed rectifier K+ current (IKs) ensures repolarization of action potential during beta-adrenergic activation or when other repolarizing K+ currents fail. As a key factor of cardiac repolarization IKs should be present in model species used for cardiovascular drug screening, preferably with pharmacological characteristics similar to those of the human IKs. To this end, we investigated the effects of inhibitors and activators of the IKs on KCNQ1 and KCNQ1+KCNE1 channels of the zebrafish, an important model species, in Chinese hamster ovary cells. Inhibitors of IKs, chromanol 293B and HMR-1556, inhibited zebrafish IKs channels with approximately similar potency as that of mammalian IKs. Chromanol 293B concentration for half-maximal inhibition (IC50) of zebrafish IKs was at 13.1{+/-}5.8 and 13.4{+/-}2.8 M for KCNQ1 and KCNQ1+KCNE1 channels, respectively. HMR-1556 was a more potent inhibitor of zebrafish IKs with IC50=0.1{+/-}0.1 M and 1.5{+/-}0.8 M for KCNQ1 and KCNQ1+KCNE1 channels, respectively. R-L3 and mefenamic acid, generally identified as IKs activators, both inhibited zebrafish IKs. R-L3 almost completely inhibited zebrafish IKs generated by KCNQ1 and KCNQ1+KCNE1 channels with similar affinity (IC50 1.1{+/-}0.4 and 1.0{+/-}0.4 M, respectively). Mefenamic acid partially blocked zebrafish KCNQ1 (IC50=9.5{+/-}4.8 M) and completely blocked KCNQ1+KCNE1 channels (IC50=3.3{+/-}1.8 M). Although zebrafish IKs responds to IKs inhibitors in the same way as mammalian IKs, its response to activators is atypical, probably due to the differences in the binding domain of KCNE1 to KCNQ1. Therefore, care must be taken when translating the results from zebrafish to humans.

physiology↗

bioRxiv2020

Effects of Na+ channel isoforms and lipid membrane environment on temperature tolerance of cardiac Na+ current in zebrafish (Danio rerio) and rainbow trout (Oncorhynchus mykiss)

Heat tolerance of heart rate in fish is suggested to be limited by impaired electrical excitation of the ventricle due to the antagonistic effects of high temperature on Na+ (INa) and K+ (IK1) ion currents (INa is depressed at high temperatures while IK1 is resistant to them). To examine the role of Na+ channel proteins and the lipid matrix of the channels in heat tolerance of INa, we compared temperature-dependencies of zebrafish (Danio rerio) and rainbow trout (Oncorhynchus mykiss) ventricular INa, and INa generated by the cloned zebrafish and rainbow trout NaV1.4 and NaV1.5 Na+ channels in HEK cells. Whole-cell patch clamp recordings showed that zebrafish ventricular INa has better heat tolerance and slower inactivation kinetics than rainbow trout ventricular INa. In contrast, heat tolerance and inactivation kinetics of zebrafish and rainbow trout NaV1.4 channels are similar when expressed in the identical plasma membrane lipid matrix of HEK cells. The same applies to NaV1.5 channels. Thermal adaptation of the ventricular INa is largely achieved by differential expression of Na+ channel alpha subunits: zebrafish which tolerate well high temperatures mainly express the slower NaV1.5 isoform, while rainbow trout which prefer cold waters mainly express the faster NaV1.4 isoform. Differences in elasticity (stiffness) of the lipid bilayer may be also involved in thermal adaptation of INa. These findings suggest that both the protein component and its lipid bilayer matrix are involved in thermal adaptation of the voltage-gated Na+ channels and therefore in heart rate regulation under thermal stress in fish.

physiology↗