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Br J Pharmacol
2014 Dec 01;17123:5182-94. doi: 10.1111/bph.12596.
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Modulation of K2P 2.1 and K2P 10.1 K(+) channel sensitivity to carvedilol by alternative mRNA translation initiation.
Kisselbach J
,
Seyler C
,
Schweizer PA
,
Gerstberger R
,
Becker R
,
Katus HA
,
Thomas D
.
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BACKGROUND AND PURPOSE: The β-receptor antagonist carvedilol blocks a range of ion channels. K2P 2.1 (TREK1) and K2P 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 K2P 2.1 and K2P 10.1 channels. Second, we sought to study ATI-dependent modulation of K2P K(+) current sensitivity to carvedilol.
EXPERIMENTAL APPROACH: Using standard electrophysiological techniques, we recorded currents from wild-type and mutant K2P 2.1 and K2P 10.1 channels in Xenopus oocytes and HEK 293 cells.
KEY RESULTS: Carvedilol concentration-dependently inhibited K2P 2.1 channels (IC50 ,oocytes = 20.3 μM; IC50 , HEK = 1.6 μM) and this inhibition was frequency-independent. When K2P 2.1 isoforms generated by ATI were studied separately in oocytes, the IC50 value for carvedilol inhibition of full-length channels (16.5 μM) was almost 5-fold less than that for the truncated channel variant (IC50 = 79.0 μM). Similarly, the related K2P 10.1 channels were blocked by carvedilol (IC50 ,oocytes = 24.0 μM; IC50 , HEK = 7.6 μM) and subject to ATI-dependent modulation of drug sensitivity.
CONCLUSIONS AND IMPLICATIONS: Carvedilol targets K2P 2.1 and K2P 10.1 K(+) channels. This previously unrecognized mechanism supports a general role of cardiac K2P channels as antiarrhythmic drug targets. Furthermore, the work reveals that the sensitivity of the cardiac ion channels K2P 2.1 and K2P 10.1 to block was modulated by alternative mRNA translation initiation.
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