Differential Expression of Voltage-Gated K
            <sup>+</sup>
            Channel Subunits in Adult Rat Heart

Barry, Dianne M.; Trimmer, James S.; Merlie, John P.; Nerbonne, Jeanne M.

doi:10.1161/01.res.77.2.361

Cited by 209 publications

(162 citation statements)

References 30 publications

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“…The molecular identity of I to is species-specific. In ferret and rat hearts the molecular correlate of I to is both Kv4.2 and Kv4.3 (24,25), whereas in the human and canine hearts Kv4.3 is the dominant isoform (26,27). Ion channels of the Shal family, Kv4.2 and Kv4.3, are regulated by a variety of extracellular factors including inhibition via ␣ 1 -adrenergic, muscarinic, endothelin, and angiotensin receptors (15, 16, 29 -32).…”

mentioning

confidence: 99%

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Doronin

Potapova

et al. 2004

Journal of Biological Chemistry

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We report a novel signal transduction complex of the angiotensin receptor type 1. In this complex the angiotensin receptor type 1 associates with the potassium channel ␣-subunit Kv4.3 and regulates its intracellular distribution and gating properties. Electrophysiological remodeling in hypertrophy and heart failure predisposes the heart to lethal arrhythmias, which account for half of the mortality (1, 2). Experimental evidence derived from large scale clinical trials shows that inhibition of angiotensin II synthesis by inhibitors of angiotensin-converting enzyme or direct blockade of angiotensin receptor type 1 (AT1 1 receptor) with the antagonist losartan protects the heart from hypertensive complications (3, 4). A substantial reduction in mortality has been attributed to a significant decrease in sudden cardiac deaths possibly because of fewer episodes of complex arrhythmias (5, 6). The positive influence of inhibition of angiotensin-converting enzyme has been linked to bradykinin-mediated effects (7,8). However, the role of direct blockade of the AT1 receptor by losartan in episodes of sudden cardiac arrhythmias is still debated (9 -11). Electrophysiologic remodeling affects the entire spectrum of cardiac ion channels including the transient outward potassium current (I to ) whose density is often decreased in heart failure (2, 12, 13).The mechanism of I to down-regulation in heart failure is not completely understood and is likely to have multiple etiologies. In part it can be explained by the inhibitory effects of angiotensin II. Experiments with spontaneously hypertensive rats suggest that the AT1 receptor might be directly involved in the regulation of I to . In this animal model I to is inhibited and can be recovered by treatment with the AT1 receptor specific antagonist losartan (14). Experiments with isolated cardiomyocytes show that stimulation of the AT1 receptor results in the inhibition of I to in myocytes from rat or canine ventricle (15,16). In large mammals such as dogs or humans with substantial ventricular wall thickness, I to exhibits a transmural gradient that is vital for normal electrical activity (17,18). Distortion of the I to gradient leads to dispersion of repolarization across the ventricular wall, providing a substrate for ventricular arrhythmias (19). In both canine and human ventricle, I to density is higher in epicardial and midmyocardial than in the endocardial cells (17,18). The gradient of I to inversely correlates with the gradient of angiotensinogen across the ventricular wall whose expression is more prominent in the subendocardial than in either midmyocardium or epicardium regions (20). Evidence exists that cardiomyocytes, Purkinje fibers, and cardiac fibroblasts produce angiotensin II (21-23). Therefore, locally produced angiotensin II could act in a paracrine and/or autocrine manner to regulate I to . Experiments in vitro show that losartan stimulates I to in canine cardiomyocytes isolated from endocardium and converts the configuration of the action potential of endocar...

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confidence: 99%

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Doronin

Potapova

et al. 2004

Journal of Biological Chemistry

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“…Kv2.1, a slow-inactivating delayed rectifier channel (16), although being widely distributed in the central nervous system, mainly on postsynaptic structures (17,18), is the prevalent Kv channel in neuroendocrine and endocrine cells (19,20). It was shown that the Kv2.1 current repolarizes ␤-cell action potentials during a glucose stimulus to limit Ca 2ϩ entry and insulin secretion (21).…”

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confidence: 99%

Direct Interaction of Target SNAREs with the Kv2.1 Channel

Michaelevski¹,

Chikvashvili²,

Tsuk³

et al. 2003

Journal of Biological Chemistry

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Previously we suggested that interaction between voltage-gated K ؉ channels and protein components of the exocytotic machinery regulated transmitter release. This study concerns the interaction between the Kv2.1 channel, the prevalent delayed rectifier K ؉ channel in neuroendocrine and endocrine cells, and syntaxin 1A and SNAP-25. We recently showed in islet ␤-cells that the Kv2.1 K ؉ current is modulated by syntaxin 1A and SNAP-25. Here we demonstrate, using co-immunoprecipitation and immunocytochemistry analyses, the existence of a physical interaction in neuroendocrine cells between Kv2.1 and syntaxin 1A. Furthermore, using concomitant co-immunoprecipitation from plasma membranes and two-electrode voltage clamp analyses in Xenopus oocytes combined with in vitro binding analysis, we characterized the effects of these interactions on the Kv2.1 channel gating pertaining to the assembly/disassembly of the syntaxin 1A/SNAP-25 (target (t)-SNARE) complex. Syntaxin 1A alone binds strongly to Kv2.1 and shifts both activation and inactivation to hyperpolarized potentials. SNAP-25 alone binds weakly to Kv2.1 and probably has no effect by itself. Expression of SNAP-25 together with syntaxin 1A results in the formation of t-SNARE complexes, with consequent elimination of the effects of syntaxin 1A alone on both activation and inactivation. Moreover, inactivation is shifted to the opposite direction, toward depolarized potentials, and its extent and rate are attenuated. Based on these results we suggest that exocytosis in neuroendocrine cells is tuned by the dynamic coupling of the Kv2.1 channel gating to the assembly status of the t-SNARE complex.The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) 1 proteins syntaxin, SNAP-25, and VAMP are crucial factors in processes of transmitter and hormone release (1). They interact with a wide range of proteins, some of them (such as synaptotagmin) associated with vesicular membranes or with plasma membranes (for example, voltage-gated Ca 2ϩ channels) (1-5). We suggested previously (6) that SNARE proteins interact with a member of the Kv1 subfamily of the voltage-gated K ϩ (Kv) channels and that these interactions may play a role in synaptic efficacy and neuronal excitability. Our results showed that in brain synaptosomes the presynaptic Kv1.1 channel (7) interacts with some of the protein components of the exocytotic apparatus, including syntaxin 1A, SNAP-25, and synaptotagmin, in a manner that is sensitive to the exocytotic state of the synaptosomes. We also showed that Kv1.1 in complex with the auxiliary Kv␤ 1.1 subunits (8) interacts directly with syntaxin 1A, and the feedback effect of this interaction on the channel function enhances its fast inactivation in Xenopus oocytes. Involvement of G protein ␤␥ subunits was found to be a requirement for this interaction (9). These characteristics of the interaction of presynaptic Kv channels with syntaxin 1A are reminiscent of the interaction of the presynaptic N-type voltage-gated Ca 2ϩ channels (10 -12)....

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“…There are >15 different potassium channel genes that have been quantitatively demonstrated to exist in rat atrial and ventricular muscles, with Kcna2, kv1.4, kv1.5, kv2.1, and kv4.2 being expressed at significant levels 7, 27. Western blot analyses of atrial and ventricular membrane proteins confirmed the presence of Kcna2 at 75 kDa in adult rat heart membranes 8. Furthermore, Kcna2 has also been observed in human ventricular tissue 5.…”

Section: Discussionmentioning

confidence: 86%

“…There is direct evidence showing that the I Ks is generated by Kcna2 in Xenopus oocytes, rabbit vascular myocytes, pulmonary arterial smooth muscle cells, rat mesenteric artery smooth muscle cells, and canine colonic circular smooth muscles 29, 30, 31, 32, 33. Specifically, Kcna2 was demonstrated to contribute to the I Ks, rather than the transient outward potassium current, in adult rat myocytes 8. We verified that Kcna2 channels encode I Ks , as shown in Figure S5.…”

Section: Discussionmentioning

confidence: 99%

“…Delayed rectifier potassium channels are important for controlling the repolarization of several ion species in the heart, and decreases in the delayed rectifier potassium current (I K ) in heart failure results in action potential (AP) prolongation, which is an important contributor to the development of ventricular arrhythmias 4, 5, 6. Kcna2, also known as Kv1.2, which is a subunit of the voltage‐gated shaker channel family, is one of the dominant ion channels in cardiac muscle and encodes I K 7, 8. The expression levels of myocardial Kcna2 are decreased in hypertrophic cardiac tissue, senescent hearts, diabetic hearts, and patients with obesity‐induced cardiomyopathy,9, 10, 11, 12 indicating that Kcna2 might be a key regulator of ventricular arrhythmias in CHF.…”

Section: Introductionmentioning

confidence: 99%

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Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure

Long

Wang

Gao

et al. 2017

JAHA

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BackgroundCongestive heart failure (CHF) is a common cardiovascular disease that is often accompanied by ventricular arrhythmias. The decrease of the slow component of the delayed rectifier potassium current (IK s) in CHF leads to action potential (AP) prolongation, and the IK s is an important contributor to the development of ventricular arrhythmias. However, the molecular mechanisms underlying ventricular arrhythmias are still unknown.Methods and ResultsKcna2 and Kcna2 antisense RNA (Kcna2 AS) transcript expression was measured in rat cardiac tissues using quantitative real‐time reverse transcription–polymerase chain reaction and Western blotting. There was a 43% reduction in Kcna2 mRNA in the left ventricular myocardium of rats with CHF. Kcna2 knockdown in the heart decreased the IKs and prolonged APs in cardiomyocytes, consistent with the changes observed in heart failure. Conversely, Kcna2 overexpression in the heart significantly attenuated the CHF‐induced decreases in the IKs, AP prolongation, and ventricular arrhythmias. Kcna2 AS was upregulated ≈1.7‐fold in rats with CHF and with phenylephrine‐induced cardiomyocyte hypertrophy. Kcna2 AS inhibition increased the CHF‐induced downregulation of Kcna2. Consequently, Kcna2 AS mitigated the decrease in the IKs and the prolongation of APs in vivo and in vitro and reduced ventricular arrhythmias, as detected using electrocardiography.ConclusionsVentricular Kcna2 AS expression increases in rats with CHF and contributes to reduced IK s, prolonged APs, and the occurrence of ventricular arrhythmias by silencing Kcna2. Thus, Kcna2 AS may be a new target for the prevention and treatment of ventricular arrhythmias in patients with CHF.

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Differential Expression of Voltage-Gated K ⁺ Channel Subunits in Adult Rat Heart

Cited by 209 publications

References 30 publications

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Direct Interaction of Target SNAREs with the Kv2.1 Channel

Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure

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Differential Expression of Voltage-Gated K + Channel Subunits in Adult Rat Heart

Cited by 209 publications

References 30 publications

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Direct Interaction of Target SNAREs with the Kv2.1 Channel

Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure

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Differential Expression of Voltage-Gated K ⁺ Channel Subunits in Adult Rat Heart