Year: 2018
Type: article
Abstract: Polyunsaturated fatty acid (PUFA) analogs represent a new class of potential anti-arrhythmic K V 7.1 and K V 7.1+KCNE1 channel activators. In this study, we describe dual independent activating effects of negatively charged PUFA analogs on K V 7.1 and K V 7.1+KCNE1 that are dependent on discrete channel motifs. PUFA analogs are critically dependent on K326 in S6 of K V 7.1 to increase the maximum conductance and critically dependent on specific S4 arginines in K V 7.1 to shift the voltage dependence of channel opening toward negative voltages. Our findings provide insights into how K V 7.1+KCNE1 activators may interact electrostatically both with the pore domain and the voltage-sensing domain to augment channel activity. We believe that the molecular understanding of how PUFA analogs induce dual independent activating effects is an important step toward the development of effective anti-arrhythmic drugs that target K V 7.1 channels.
Source: Cell Reports
Institutions: Linköping University, University of Miami
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,765
Funders: American Heart Association, Northwest Lions Foundation, Lions Clubs International Foundation, Svenska Sällskapet för Medicinsk Forskning, Vetenskapsrådet, Magnus Bergvalls Stiftelse, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences
OpenAlex ID: W2889617033