Modulation of K2P K+ Leak Channel Sensitivity to Carvedilol by Alternative MRNA Translation Initiation

Abstract

The β-receptor antagonist carvedilol exerts multichannel blocking properties. K2P2.1 (TREK1) and K2P10.1 (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 K2P2.1 and K2P10.1 channels. Second, we sought to study ATI-dependent modulation of K2P K+ current sensitivity to carvedilol.Wild type and mutant K2P2.1 and K2P10.1 currents were recorded from Xenopus oocytes and HEK 293 cells. Carvedilol caused concentration-dependent inhibition of K2P2.1 channels (IC50,oocytes = 20.3 µM; IC50,HEK = 1.6 µM). The drug targeted K2P2.1 channels in voltage-dependent and frequency-independent fashion. When K2P2.1 isoforms generated by ATI were studied in isolation in oocytes, the IC50 value for carvedilol inhibition of full-length channels (16.5 µM) differed by 4.8-fold from the truncated channel variant (IC50 = 79.0 µM). Similarly, related K2P10.1 channels were blocked by carvedilol (IC50,oocytes = 24.0 µM; IC50,HEK = 7.6 µM) and subject to ATI-dependent modulation of drug sensitivity.In conclusion, carvedilol targets K2P2.1 and K2P10.1 K+ channels. Drug sensitivity of cardiac ion channels K2P2.1 and K2P10.1 is modulated by alternative mRNA translation initiation.