Several β-subunits have been suggested to modulate the electrophysiological properties of the transient outward current (Ito) in cardiac myocytes, including the obligatory β-subunit K+-channel interacting protein (KChIP2) and KCNE2. However, neither KChIP2 nor KCNE2 modulation of Kv4.x (x=2 and/or 3) can fully recapitulate the electrophysiological properties of native Ito. The present study is to investigate how Ito current is modulated when both KChIP2 and KCNE2 are co-expressed.
Kv4.2, KChIP2c, and KCNE2 cDNA were simultaneously transfected into COS-7 cells at a molar ratio of 3:1:1. Whole-cell currents were recorded by the patch-clamp method.
In comparison with the current regulated by KChIP2c alone, the co-expression of KCNE2 further slowed Kv4.2 current inactivation kinetics, but diminished KChIP2c-induced positive shift of the voltage-dependent activation of Kv4.2 current. Importantly, co-expression of KCNE2 accelerated the current recovery from inactivation, and caused an “overshoot” of peak current amplitude during Kv4.2 current recovery, a phenomenon which has been uniquely described for human Ito. However, co-expression of KCNE2 exerted no further effect on Kv4.2 current amplitude, the rate of Kv4.2 current activation and voltage-dependent inactivation.
Co-expression of Kv4.2 with KChIP2c and KCNE2, but not with KChIP2c or KCNE2 alone, yields a current profile similar to native Ito. Both KChIP2c and KCNE2 simultaneously participate in recapitulation of the electrophysiological properties of Ito in cardiac myocytes.
Barry DM, Trimmer JS, Merlie JP, Nerbonne JM . Differential expression of voltage-gated K+ channel subunits in adult rat heart: relation to functional K+ channels? Circ Res 1995; 77: 361–9.
Dixon JE, Shi W, Wang HS, McDonald C, Yu H, Wymore RS, et al. Role of the Kv4.3 K+ channel in ventricular muscle: A molecular correlate for the transient outward current. Circ Res 1996; 79: 659–68.
An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, et al. Modulation of A-type potassium channels by a family of calcium sensors. Nature 2000; 403: 553–6.
Deschênes I, DiSilvestre D, Juang GJ, Wu RC, An WF, Tomaselli GF . Regulation of Kv4.3 current by KChIP2 splice variants: A component of native cardiac I to? Circulation 2002; 106: 423–9.
Jiang M, Zhang M, Tang DG, Clemo HF, Liu J, Holwitt D, et al. KCNE2 protein is expressed in ventricles of different species, and changes in its expression contribute to electrical remodeling in diseased hearts. Circulation 2004; 109: 1783–8.
Zhang M, Jiang M, Tseng GN . MinK-related peptide 1 associates with Kv4.2 and modulates its gating function: potential role as β subunit of cardiac transient outward channel? Circ Res 2001; 88: 1012–9.
Liu J, Deng JX, Pan BX, Huang QB . KCNE2 modulates the function of Kv4.3 channel. J South Med Univ 2006; 26: 1754–6 (in Chinese).
Patel SP, Campbell DL, Morales MJ, Strauss HC . Heterogeneous expression of KChIP2 isoforms in the ferret heart. J Physiol 2002; 539: 649–56.
Rosati B, Grau F, Rodriguez S, Li H, Nerbonne JM, McKinnon D . Concordant expression of KChIP2 mRNA, protein and transient outward current throughout the canine ventricle. J Physiol 2003; 548: 815–22.
Rosati B, Pan Z, Lypen S, Wang HS, Cohen I, Dixon JE, et al. Regulation of KChIP2 potassium channel beta subunit gene expression underlies the gradient of transient outward current in canine and human ventricle. J Physiol 2001; 533: 119–25.
Wetter E, Amos GJ, Posival H, Ravens U . Transient outward current in human ventricular myocytes of subepicardial and sub-endocardial origin. Circ Res 1994; 75: 473–82.
Radicke S, Cotella D, Graf EM, Banse U, Jost N, Varro A, et al. Functional modulation of the transient outward current I to by KCNE β-subunits and regional distribution in human non-failing and failing hearts. Cardiovasc Res 2006; 71: 695–703.
Wickenden AD, Jegla TJ, Kaprielian R, Backx PH . Regional contributions of Kv1.4, Kv4.2, and Kv4.3 to transient outward K+ current in rat ventricle. Am J Physiol 1999; 276: H1599–H1607.
Liu XS, Jiang M, Zhang M, Tang D, Clemo HF, Higgins RSD, et al. Electrical remodeling in a canine model of ischemic cardiomyopathy. Am J Physiol Heart Circ Physiol 2007; 292: H560–71.
Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, et al. MiRP1 forms I Kr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999; 97: 175–87.
Project supported by the National Natural Science Foundation of China (No 30570418 and 30570940).
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Liu, Wj., Wang, Ht., Chen, Ww. et al. Co-expression of KCNE2 and KChIP2c modulates the electrophysiological properties of Kv4.2 current in COS-7 cells. Acta Pharmacol Sin 29, 653–660 (2008). https://doi.org/10.1111/j.1745-7254.2008.00804.x
- transient outward current
- K+-channel interacting protein
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