Modulation of K2P2.1 and K2P10.1 K+ channel sensitivity to carvedilol by alternative mRNA translation initiation. (28th August 2014)

• Record Type: Journal Article
• Authors: Kisselbach, J; Seyler, C; Schweizer, P A; Gerstberger, R; Becker, R; Katus, H A; Thomas, D
• Is Part Of: British journal of pharmacology. Volume 171:Number 23(2014:Dec.)
• Page Start: 5182
• Page End: 5194
• Publication Date: 2014-08-28
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12596
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12596-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>The β‐receptor antagonist carvedilol blocks a range of ion channels. K<sub>2P</sub>2.1 (TREK1) and K<sub>2P</sub>10.1 (TREK2) channels are expressed in the heart and regulated by alternative translation initiation (ATI) of their mRNA, producing functionally distinct channel variants. The first objective was to investigate acute effects of carvedilol on human K<sub>2P</sub>2.1 and K<sub>2P</sub>10.1 channels. Second, we sought to study ATI‐dependent modulation of K<sub>2P</sub> K<sup>+</sup> current sensitivity to carvedilol.</p> </sec> <sec id="bph12596-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>Using standard electrophysiological techniques, we recorded currents from wild‐type and mutant K<sub>2P</sub>2.1 and K<sub>2P</sub>10.1 channels in <italic>X</italic><italic>enopus</italic> oocytes and HEK 293 cells.</p> </sec> <sec id="bph12596-sec-0003" sec-type="section"> <title>Key Results</title> <p>Carvedilol concentration‐dependently inhibited K<sub>2P</sub>2.1 channels (IC<sub>50</sub><sub>, oocytes</sub> = 20.3 μM; IC<sub>50</sub><sub>, </sub><sub>HEK</sub> = 1.6 μM) and this inhibition was frequency‐independent. When K<sub>2P</sub>2.1 isoforms generated by ATI were studied separately in oocytes, the IC<sub>50</sub> value for carvedilol inhibition of full‐length channels (16.5 μM) was almost 5‐fold less than that for the truncated channel variant (IC<sub>50</sub> = 79.0 μM). Similarly, the related K<sub>2P</sub>10.1 channels were blocked by carvedilol (IC<sub>50</sub><sub>, oocytes</sub> = 24.0 μM; IC<sub>50</sub><sub>, </sub><sub>HEK</sub> = 7.6 μM) and subject to ATI‐dependent modulation of drug sensitivity.</p> </sec> <sec id="bph12596-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>Carvedilol targets K<sub>2P</sub>2.1 and K<sub>2P</sub>10.1 K<sup>+</sup> channels. This previously unrecognized mechanism supports a general role of cardiac K<sub>2P</sub> channels as antiarrhythmic drug targets. Furthermore, the work reveals that the sensitivity of the cardiac ion channels K<sub>2P</sub>2.1 and K<sub>2P</sub>10.1 to block was modulated by alternative mRNA translation initiation.</p> </sec> </abstract>