L-Type Ca2+Channel α1cSubunit Isoform Switching in Failing Human Ventricular Myocardium

Yang, Yingbo; Chen, Xiongwen; Margulies, Kenneth B.; Jeevanandam, Valvulan; Pollack, Pia S.; Bailey, Beth A.; Houser, Steven R.

doi:10.1006/jmcc.2000.1138

Cited by 83 publications

(57 citation statements)

References 24 publications

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“…Christ et al (105), on the contrary, suggest that an increase in protein phosphatase 2A activity contributes to the impaired I Ca density in AF, which may imply reduced single-channel activity. Overall, based on the results available to date, it appears there are other regulatory pathways and factors impacting the L-VDCC during AF and heart failure (108)(109)(110). It is of considerable interest that, after the many years since the cloning of the L-VDCC, a mutation has finally been demonstrated in the α 1C subunit (111).…”

Section: L-vdcc In Afmentioning

confidence: 99%

The L-type calcium channel in the heart: the beat goes on

Bódi¹

2005

Journal of Clinical Investigation

255

213

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Sydney Ringer would be overwhelmed today by the implications of his simple experiment performed over 120 years ago showing that the heart would not beat in the absence of Ca 2+ . Fascination with the role of Ca 2+ has proliferated into all aspects of our understanding of normal cardiac function and the progression of heart disease, including induction of cardiac hypertrophy, heart failure, and sudden death. This review examines the role of Ca 2+ and the L-type voltage-dependent Ca 2+ channels in cardiac disease.When Sydney Ringer (1) discovered the vital role of Ca 2+ in the heart, investigations took a leap forward and have continued unabated (2). Austrian scientist Otto Loewi, best known for his work on autonomic transmitters and discovery of "chemical vagusstoff," recognized the connection between digitalis and Ca 2+ in [1917][1918]. Although he always believed that Ca 2+ was the key to understanding life's processes, the Nobel Prize in Physiology and Medicine was awarded to Loewi and Sir Henry Hallett Dale in 1936 for their studies on neurotransmitters.Ca 2+ is the link in excitation-contraction (EC) coupling (Figure 1), which starts during the upstroke of the action potential (AP) and causes the opening of the L-type voltage-dependent Ca 2+ channel (L-VDCC). Interest in high-voltage-activated L-VDCCs began with biochemical and continued with molecular characterizations, culminating in the cloning of the pore-forming α 1 subunit and the auxiliary channel subunit α 2 /δ from rabbit skeletal muscle (3)(4)(5). Although the L-VDCC subunits are most abundant in fast skeletal transverse tubules, Ca 2+ influx is not required for contraction in skeletal muscle, unlike cardiac muscle, which requires Ca 2+ entry with each beat and triggers Ca 2+ release from the sarcoplasmic reticulum (SR) via Ca 2+ -release channels, e.g., ryanodine receptor 2 (RyR2). This amplifying process, termed Ca 2+ -induced Ca 2+ release (CICR) by A. Fabiato, causes a rapid increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) (from ∼100 nM to ∼1 µM) to a level required for optimal binding of Ca 2+ to troponin C and induction of contraction (2). There is a close correlation between activation of the L-type Ca 2+ current (I Ca,L ) and cardiac contraction. Contraction is followed by Ca 2+ release from troponin C and its reuptake by the SR via activation of the SR Ca 2+ -ATPase 2a (SERCA2a) Ca 2+ pump in addition to extrusion across the sarcolemma via the Na + /Ca 2+

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Section: L-vdcc In Afmentioning

confidence: 99%

The L-type calcium channel in the heart: the beat goes on

Bódi¹

2005

Journal of Clinical Investigation

255

213

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“…Changes in channel subunit isoforms can also contribute to this behavior. Alternative isoforms of the pore-forming Ca v 1.2 channel have been demonstrated in failing hearts, 19 and additionally, auxiliary subunits may have important modulatory roles. For example, overexpression of the ␤ 2a subunit in rat ventricular myocytes can clearly increase current levels.…”

Section: Basal Regulation Of L-type Ca 2؉ Channelsmentioning

confidence: 99%

L-Type Ca ²⁺ Channels Gaining Respect in Heart Failure

Kamp

2002

Circulation Research

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channel abundance and function in heart failure. 5,6 To appreciate the story, one needs to step back from the macroscopic or whole-cell currents through L-type Ca 2ϩ channels and look behind the scenes. Whole-cell currents are determined by the number of functional channels (N), the probability of a channel being open (p o ), and the current through a single open channel (i) as described by the following simple relationship: I Ca,L ϭN*p o *i. Thus, the finding that peak I Ca is comparable in failing and nonfailing myocytes when measured using standard voltage-clamp techniques may in fact be hiding counterbalancing changes in channel density, gating, and singlechannel current. It is also important to realize that the altered conformation of the action potential in failing myocytes can have a large effect on the influx of Ca 2ϩ through L-type Ca 2ϩ channels even if all of the properties of the channels are unchanged. 7,8 Tracking the Density and Gating of L-Type Ca 2؉ ChannelsA number of techniques exist that provide detailed information on the number and gating of L-type Ca 2ϩ channels. Biochemical techniques have generally suggested no change or a decrease in protein abundance of channel subunits or binding sites for Ca 2ϩ antagonists in failing hearts 2 ; however, it is difficult to extrapolate these results to functional channels at the surface membrane. A single-channel electrophysiological study provided the first clue that the story on L-type Ca 2ϩ channels may be more complicated than originally suspected. It was demonstrated that the number of functional channels and the open probability of the channels were markedly increased in failing human ventricular myocytes without changes in single-channel current, just as if the channels had been stimulated by protein kinase A (PKA)-dependent phosphorylation. 6 Given that the whole-cell currents were unchanged, the authors speculated that the density of channels is decreased in failing cells with a compensatory increase in the availability and open probability of the remaining channels. The limitation of that study was that by necessity the single-channel recordings were made from channels on the surface sarcolemma, whereas most of Ca 2ϩ channels are concentrated in the t-tubules in ventricular myocytes where the majority of EC coupling action occurs.An alternative approach measuring intramembrane charge movement associated with L-type Ca 2ϩ channels was taken in the tachycardia-pacing canine heart failure model. 5 With appropriate voltage protocols, maximal intramembrane charge movement should be directly proportional to L-type Ca 2ϩ channel number. Despite finding a comparable density of I Ca in control and failing myocytes as had others, 9 the study showed more than a 50% decrease in maximal amount of intramembrane charge movement again suggesting that the overall density of L-type Ca 2ϩ channels is significantly decreased. The limitation of the charge movement study is that it is difficult to isolate charge movement due to L-type Ca 2ϩ channels in myocytes th...

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“…Previous studies have shown that atherosclerosis and heart failure alter Ca V 1.2 exon expression (30,38). Exons 9* and 41a are detected in normal human arterial smooth muscle cells but are absent in smooth muscle cells located in atherosclerotic regions (30).…”

Section: Discussionmentioning

confidence: 98%

“…In contrast, exon 22 is absent in normal human arterial smooth muscle cells but is detected in cells from atherosclerotic areas (30). A switch between exons 31 and 32 has also been observed in heart failure, with the former being ϳ2.5 times more abundant in nonfailing human ventricle and the latter being twice as abundant in failing hearts (38). Our determination of the combinatorial profiles of Ca V 1.2 splice variants in cerebral artery smooth muscle cells becomes important not only to determine contributions to tissue physiology and pharmacology but also as a first step in the identification of exon switches that may occur in disease.…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing of Ca_v1.2 channel exons in smooth muscle cells of resistance-size arteries generates currents with unique electrophysiological properties

Cheng¹,

Pachuau²,

Blaskova³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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2) channels are the primary Ca 2ϩ entry pathway in smooth muscle cells of resistance-size (myogenic) arteries, but their molecular identity remains unclear. Here we identified and quantified Ca V1.2 ␣1-subunit splice variation in myocytes of rat resistance-size (100 -200 m diameter) cerebral arteries. Full-length clones containing either exon 1b or the recently identified exon 1c exhibited additional primary splice variation at exons 9*, 21/22, 31/32, and Ϯ 33. Real-time PCR confirmed the findings from full-length clones and indicated that the major CaV1.2 variant contained exons 1c, 8, 21, and 32ϩ33, with ϳ57% containing 9*. Exon 9* was more prevalent in clones containing 1c (72%) than in those containing 1b (33%), suggesting exon-selective combinatorial splicing. To examine the functional significance of this splicing profile, membrane currents produced by each of the four exon 1b/c/ Ϯ 9* variants were characterized following transfection in HEK293 cells. Exon 1c and 9* caused similar hyperpolarizing shifts in both current-voltage relationships and voltage-dependent activation of currents. Furthermore, exon 9* induced a hyperpolarizing shift only in the voltage-dependent activation of channels containing exon 1b, but not in those containing exon 1c. In contrast, exon 1b, 1c, or ϩ9* did not alter voltagedependent inactivation. In summary, we have identified the CaV1.2 ␣1-subunit splice variant population that is expressed in myocytes of resistance-size arteries and the unique electrophysiological properties of recombinant channels formed by exon 1 and 9* variation. The predominance of exon 1c and 9* in smooth muscle cell CaV1.2 channels causes a hyperpolarizing shift in the voltage sensitivity of currents toward the physiological arterial voltage range.voltage-dependent calcium channel; myogenic artery; cloning; ribonucleic acid splicing L-TYPE, VOLTAGE-GATED Ca 2ϩ channels are expressed in multiple cell types, including neurons, cardiac myocytes, and smooth muscle cells (6). In vascular smooth muscle cells, L-type Ca 2ϩ (Ca v 1.2) channels provide the major Ca 2ϩ entry pathway (13,22,23). Ca 2ϩ influx via Ca v 1.2 channels regulates multiple smooth muscle functions, including contractility and gene expression (26,32). Indeed, Ca v 1.2 channels play a critical role in mediating myogenic tone development in small, resistancesize arteries and arterioles that regulate blood pressure and organ blood flow (4, 21). In systemic hypertension, arteries display elevated Ca V 1.2 channel expression and arterial smooth muscle cells exhibit an increase in L-type Ca 2ϩ current density, consistent with increased contractility (24). In addition, because of their ability to block Ca V 1.2 channels and reduce Ca 2ϩ influx, voltage-dependent Ca 2ϩ channel blockers are effective for alleviating hypertension and other cardiovascular diseases associated with increased vascular tone, including some forms of angina (31). However, despite the importance of Ca V 1.2 channels in regulating arterial smooth muscle physiology and evidence t...

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L-Type Ca2+Channel α1cSubunit Isoform Switching in Failing Human Ventricular Myocardium

Cited by 83 publications

References 24 publications

The L-type calcium channel in the heart: the beat goes on

The L-type calcium channel in the heart: the beat goes on

L-Type Ca ²⁺ Channels Gaining Respect in Heart Failure

Alternative splicing of Ca_v1.2 channel exons in smooth muscle cells of resistance-size arteries generates currents with unique electrophysiological properties

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L-Type Ca2+Channel α1cSubunit Isoform Switching in Failing Human Ventricular Myocardium

Cited by 83 publications

References 24 publications

The L-type calcium channel in the heart: the beat goes on

The L-type calcium channel in the heart: the beat goes on

L-Type Ca 2+ Channels Gaining Respect in Heart Failure

Alternative splicing of Cav1.2 channel exons in smooth muscle cells of resistance-size arteries generates currents with unique electrophysiological properties

Contact Info

Product

Resources

About

L-Type Ca ²⁺ Channels Gaining Respect in Heart Failure

Alternative splicing of Ca_v1.2 channel exons in smooth muscle cells of resistance-size arteries generates currents with unique electrophysiological properties