Cloning of the β2a Subunit of the Voltage-Dependent Calcium Channel from Human Heart: Cooperative Effect of α2/δ and β2a on the Membrane Expression of the α1C Subunit

Yamaguchi, Hiroshi; Okuda, Masaru; Mikala, Gábor; Fukasawa, Kenji; Váradi, Gyula

doi:10.1006/bbrc.1999.1926

Cited by 28 publications

(30 citation statements)

References 41 publications

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“…at the respective potential of peak current density (I 100 for non-cotransfected cells, 102 Ϯ 3%; ␤ 2a , 66 Ϯ 9%; ␤ 3a , 74 Ϯ 4%; and ␤ 3trunc , 68 Ϯ 13%; n as in Fig. 3), as reported (12,25). Although the qualitative effects with cotransfection of rabbit ␤ 2a -and human ␤ 3 -subunits were similar, the effects of ␤ 3 -subunits, and of ␤ 3trunc in particular, were less pronounced.…”

Section: Resultssupporting

confidence: 68%

“…The 483-bp amplification product contained a deletion of 20 nucleotides matching exon 6 of the ␤ 3 -gene (11). At least two different isoforms of the human ␤ 2 -subunit gene are expressed in the human heart (␤ 2a , ␤ 2b ) (12,13) that differ with respect to their short amino termini. Our Northern blot experiments revealed transcripts for ␤ 2a -, ␤ 2b -, and ␤ 3 -subunits in human heart tissue; therefore, we assessed quantitative expression of these ␤-subunits by real-time PCR, which demonstrated substantially different expression levels with ␤ 2b Ͼ ␤ 3 Ͼ Ͼ ␤ 2a .…”

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confidence: 99%

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Cardiac L-type Calcium Channel β-Subunits Expressed in Human Heart Have Differential Effects on Single Channel Characteristics

Hullin

Khan²,

Wirtz

et al. 2003

Journal of Biological Chemistry

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103

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L-Type calcium channels are multiprotein complexes composed of pore-forming (Ca V 1.2) and modulatory auxiliary ␣ 2 ␦-and ␤-subunits. We demonstrate expression of two different isoforms for the ␤ 2 -subunit (␤ 2a , ␤ 2b ) and the ␤ 3 -subunit (␤ 3a , ␤ 3trunc ) in human non-failing and failing ischemic myocardium. Quantitatively, in the left ventricle expression of ␤ 2b transcripts prevails in the order of > ␤ 3 > > ␤ 2a . The expressed cardiac full-length ␤ 3 -subunit is identical to the ␤ 3a -isoform, and ␤ 3trunc results from deletion of exon 6 (20 nn) entailing a reading frameshift and translation stop at nucleotide position 495. In failing ischemic myocardium ␤ 3trunc expression increases whereas overall ␤ 3 expression remains unchanged. Heterologous coexpression studies demonstrated that ␤ 2 induced larger currents through rabbit and human cardiac Ca V 1.2 pore subunits than ␤ 3 isoforms. All ␤-subunits increased channel availability at single channel level, but ␤ 2 exerted an additional, marked stimulation of rapid gating (open and closed times, first latency), leading to higher peak current values. We conclude that cardiac ␤-subunit isoforms differentially modulate calcium inward currents because of regulatory effects within the channel protein complex. Moreover, differences in the various ␤-subunit gene products present in human heart might account for altered single channel behavior found in human heart failure.

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Section: Resultssupporting

confidence: 68%

mentioning

confidence: 99%

Cardiac L-type Calcium Channel β-Subunits Expressed in Human Heart Have Differential Effects on Single Channel Characteristics

Hullin

Khan²,

Wirtz

et al. 2003

Journal of Biological Chemistry

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103

110

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“…The 2 (Cacna2d) auxiliary subunit is known to increase the peak ICa,L density and to shift the voltage dependence of inactivation and activation to a more hyperpolarized level. 13,14 Also, the peak ICa,L density is known to be increased by co-expression of the (Cacnb) auxiliary subunit, [14][15][16] although there have been contro- versial results reported for 3 (Cacnb3). 17 On the basis of these reports, the present electrophysiological observations would be explained simply by the decreased amount of the main subunit 1C (Cacna1c) (Cav1.2) in the atrium being compensated for by the increased auxiliary subunit 2 (Cacna2d), leading to similar ICa,L density in the atrium and the ventricle.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Electrophysiological Differences in the L-Type Ca<sup>2+</sup> Channel of the Atrium and Ventricle of Rat Hearts

Hatano

Yamashita

Sekiguchi

et al. 2006

Circ J

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he L-type Ca 2+ channel expressed in cardiac muscle plays an important role in determining the intracellular Ca 2+ and thus the action potential duration of cardiomyocytes. 1 Although Ca 2+ overload is a major cause of myocardial cell injury, 2 blocking this channel could be either beneficial or detrimental. In fact, the available L-type Ca 2+ channel blockers should be useful for treating several types of cardiac arrhythmias, but might cause negative inotropic effects that lead to pump failure. A T-type Ca 2+ channel blocker, mibefradil, has shown potential for preventing tachycardia-induced atrial fibrillation remodeling, 3 although its underlying mechanism of prevention remains unclear. Because the T-type Ca 2+ channel blockers are one of the "atrium specific Ca 2+ channel blockers", regional differences in the L-type Ca 2+ channel blocker, if any, would open a new paradigm for controlling regional intracellular Ca 2+ .The function of the L-type Ca 2+ channel is characterized by its main subunit, 1C (Cacna1c) (Cav1.2), and also the auxiliary subunits 2 (Cacna2d) and (Cacnb). However, there are few reports investigating regional differences in Ca 2+ channel composition. Because previous studies have focused on regional or developmental differences of a single subunit, 4,5 it would be inappropriate to discuss regional differences of the L-type Ca 2+ channel with special reference to the relative expression of the composite subunits. In the present study, to determine whether the composition of the L-type Ca 2+ channel is identical throughout the heart, we analyzed both the distribution of the mRNAs and proteins that comprise the L-type Ca 2+ channel and its electrophysiological properties in rat atria and ventricles. Methods mRNA Analysis and Ribonuclease Protection AssayHearts were harvested from 10-week-old female SpragueDawley (SD) rats. For mRNA analysis, the excised hearts were divided into the sinus-node, the right atrium, the left atrium, the intraventricular septum, the epicardial side of the left ventricular free wall, the endocardial side, the left Methods and ResultsTo determine whether the L-type Ca 2+ channel is identical throughout the heart, the distribution of the mRNAs and proteins comprising the L-type Ca 2+ channel and its electrophysiological properties were analyzed in rat atria and ventricles. The mRNA of 2 -2 (Cacna2d2) was more abundantly expressed in the atrium (~5-fold) than in the ventricle. In contrast, 1C (Cacna1c) (Cav1.2) mRNA was significantly less abundant in the atrium. The level of the 1C (Cacna1c) (Cav1.2) protein was decreased (~0.5-fold) and that of 2 -1 (Cacna2d1) was increased (~2-fold) in the atrium compared with the ventricle. Although the peak ICa,L density showed no significant differences, voltage dependence of inactivation and activation of the current showed a more depolarized shift in the atrium than in the ventricle. Conclusion These results indicate that in the rat heart the L-type Ca 2+ channel differs between the atrium and ventricle with regard to gene expre...

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“…In addition, the ␤ 2a (32) and ␤ 2c (23) subunits have been cloned from human heart. Among them, the N-terminal region of the rat ␤ 2c subunit was identical to the human ␤ 2c subunit except for some differences considered to be species-specific.…”

Section: Discussionmentioning

confidence: 99%

Cloning of a Functional Splice Variant of L-type Calcium Channel β2 Subunit from Rat Heart

Yamada

Nagashima

Tsutsuura

et al. 2001

Journal of Biological Chemistry

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L-type Ca2؉ channels are heteromultimeric and finely tuned by auxiliary subunits in different tissues and regions. Among auxiliary subunits, ␤ subunit has been shown to play important roles in many functional aspects of Ca 2؉ channel. Rat heart was reported to specifically express ␤ 2a subunit. However, the slow inactivation rates of Ca 2؉ currents recorded from recombinant Ca 2؉ channels with the ␤ 2a subunit, and the reported inability to detect ␤ 2a subunit in rabbit heart by reverse transcription-PCR analysis raise the possibility of the existence of other ␤ subunits. We cloned a splice variant of ␤ 2 subunit from rat heart, using rapid amplification of cDNA 5 ends. The splice variant is highly similar to human ␤ 2c subunit that was cloned from human ventricle. Northern blot analysis detected the rat ␤ 2c subunit abundantly in rat heart and brain. The deduced amino acid sequence of the ␤ 2c subunit was different from that of the ␤ 2a subunit only in the N-terminal region. When the ␤ 2c subunit was expressed along with ␣ 1c and ␣ 2 ␦ subunits in baby hamster kidney cells, the inactivation rates were comparable with those from native cardiac myocytes, although those with the ␤ 2a subunit were slow. Taken together, these observations suggest that the ␤ 2c subunit is a functional ␤ 2 subunit expressed in heart and that the short N-terminal region plays a major role in modifying inactivation kinetics.

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Cloning of the β2a Subunit of the Voltage-Dependent Calcium Channel from Human Heart: Cooperative Effect of α2/δ and β2a on the Membrane Expression of the α1C Subunit

Cited by 28 publications

References 41 publications

Cardiac L-type Calcium Channel β-Subunits Expressed in Human Heart Have Differential Effects on Single Channel Characteristics

Cardiac L-type Calcium Channel β-Subunits Expressed in Human Heart Have Differential Effects on Single Channel Characteristics

Molecular and Electrophysiological Differences in the L-Type Ca<sup>2+</sup> Channel of the Atrium and Ventricle of Rat Hearts

Cloning of a Functional Splice Variant of L-type Calcium Channel β2 Subunit from Rat Heart

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