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

Hullin, Roger; Khan, Ismail F.; Wirtz, Susanne; Mohaçsi, Paul; Váradi, Gyula; Schwartz, Arnold; Herzig, Stefan

doi:10.1074/jbc.m211164200

Cited by 103 publications

(118 citation statements)

References 36 publications

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“…The fraction of active sweeps within a channel-containing patch (availability), the open probability within active sweeps (open probability), and the peak value of single-channel ensemble average currents (I peak ) were determined as described (35). In double-channel patches, these parameters were corrected for the number of channels as described (36). Time constants of openand closed-time histograms were estimated by the maximumlikelihood method (37).…”

Section: Methodsmentioning

confidence: 99%

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Foerster

Groner

Matthes

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Two subtypes of ␤-adrenoceptors, ␤1 and ␤2, mediate cardiac catecholamine effects. These two types differ qualitatively, e.g., regarding G protein coupling and calcium channel stimulation. Transgenic mice overexpressing human ␤2-adrenoceptors survive high-expression levels, unlike mice overexpressing ␤1-adrenoceptors. We examined the role of inhibitory Gi proteins, known to be activated by ␤2-but not ␤1-adrenoceptors, on the chronic effects of human ␤2-adrenoreceptor overexpression in transgenic mice. These mice were crossbred with mice where G␣i2, a functionally important cardiac Gi ␣-subunit, was inactivated by targeted gene deletion. Survival of ␤2-adrenoreceptor transgenic mice was reduced by heterozygous inactivation of G␣i2. Homozygous knockout͞␤2-adrenoreceptor transgenic mice died within 4 days after birth. Heterozygous knockout͞␤2-adrenoreceptor transgenic mice developed more pronounced cardiac hypertrophy and earlier heart failure compared with ␤2-adrenoreceptor transgenic mice. Single calcium-channel activity was strongly suppressed in heterozygous knockout͞␤2-adrenoreceptor transgenic mice. In cardiomyocytes from these mice, pertussis toxin treatment in vitro fully restored channel activity and enhanced channel activity in cells from homozygous G␣i2 knockout animals. Cardiac G␣i3 protein was increased in all G␣i2 knockout mouse strains. Our results demonstrate that G␣i2 takes an essential protective part in chronic signaling of overexpressed ␤2-adrenoceptors, leading to prolonged survival and delayed cardiac pathology. However, reduction of calcium-channel activity by ␤2-adrenoreceptor overexpression is due to a different pertussis-toxin-sensitive pathway, most likely by G␣i3. This result indicates that subtype-specific signaling of ␤2-adrenoreceptor functionally bifurcates at the level of Gi, leading to different effects depending on the G␣ isoform.L-type calcium channel ͉ single channel recording ͉ mouse genetics ͉ survival curve ͉ pertussis toxin C ardiac stimulatory catecholamine effects are mediated by both ␤ 1 -and ␤ 2 -adrenergic receptors (␤-adrenoceptors), mainly through cAMP-dependent protein kinase A-catalyzed phosphorylation of cardiac proteins involved in calcium homeostasis, such as phospholamban and the L-type calcium channel. Evidently, this pathway is compromised in heart failure. Because of the clear-cut evidence that ␤ 2 -adrenoceptors mediate acute functional effects in human cardiomyocyte in vitro (1, 2) and in vivo (3), a rationale for ␤ 2 -adrenoreceptor gene therapy exists (4-6). Whether and where ␤ 2 -adrenoreceptor stimulation or inhibition, by pharmacological or genetic means, will have its place in heart failure therapy is an open question (7-9).Inherent in the clinical discussion is recent molecular insight into differences between cardiac ␤ 1 -and ␤ 2 -adrenoreceptor stimulation at the signal-transduction level (10, 11). In rat cardiomyocytes, a ␤ 2 -agonist, zinterol, was shown to increase calcium current in a manner qualitatively distinct from ␤ 1 -adrenoreceptor stimu...

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Section: Methodsmentioning

confidence: 99%

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Foerster

Groner

Matthes

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…In the other study (57), β 3 -KO mice showed altered pain processing due to a decrease in the expression of N-type Ca 2+ channels via functional alterations of Ca 2+ currents in neurons projecting to the spinal cord. Expression levels of various β subunit isoforms (53,56,59) indicate that altered singlechannel behavior in human heart may be due to differential effects and changes in β subunit gene products.…”

Section: The Roles Of the β Auxiliary Subunits In Influencing Channelmentioning

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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“…Here we generated an inducible transgenic mouse to examine the effects of persistent increases in LTCC activity in the initiation and progression of heart failure. The β2a subunit of the LTCC was selected for overexpression because it enhances channel open probability and increases trafficking of the pore-forming α1c subunit to the sarcolemma, thereby causing greater Ca 2+ influx (18,32,33). A modified α-myosin heavy chain (α-MHC) promoter was used as the responder (34); when crossed with transgenic mice containing the α-MHC promoter-driven tet-transactivator protein (tTA), this produced cardiac-specific expression in the heart that was regulated by doxycycline (Dox) administration and/or withdrawal ( Figure 1A).…”

Section: Generation Of Mice With Inducible Ltcc Activitymentioning

confidence: 99%

Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure

Nakayama¹,

Chen²,

Baines³

et al. 2007

J. Clin. Invest.

377

361

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Loss of cardiac myocytes in heart failure is thought to occur largely through an apoptotic process. Here we show that heart failure can also be precipitated through myocyte necrosis associated with Ca 2+ overload. Inducible transgenic mice with enhanced sarcolemmal L-type Ca 2+ channel (LTCC) activity showed progressive myocyte necrosis that led to pump dysfunction and premature death, effects that were dramatically enhanced by acute stimulation of β-adrenergic receptors. Enhanced Ca 2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers or β-adrenergic receptor antagonists, demonstrating a proximal relationship among β-adrenergic receptor function, Ca 2+ handling, and heart failure progression through necrotic cell loss. Mechanistically, loss of cyclophilin D, a regulator of the mitochondrial permeability transition pore that underpins necrosis, blocked Ca 2+ influx-induced necrosis of myocytes, heart failure, and isoproterenol-induced premature death. In contrast, overexpression of the antiapoptotic factor Bcl-2 was ineffective in mitigating heart failure and death associated with excess Ca 2+ influx and acute β-adrenergic receptor stimulation. This paradigm of mitochondrial-and necrosis-dependent heart failure was also observed in other mouse models of disease, which supports the concept that heart failure is a pleiotropic disorder that involves not only apoptosis, but also necrotic loss of myocytes in association with dysregulated Ca 2+ handling and β-adrenergic receptor signaling.

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

Cited by 103 publications

References 36 publications

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

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

Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure

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

Cited by 103 publications

References 36 publications

Cardioprotection specific for the G protein G i2 in chronic adrenergic signaling through β 2 -adrenoceptors

Cardioprotection specific for the G protein G i2 in chronic adrenergic signaling through β 2 -adrenoceptors

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

Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure

Contact Info

Product

Resources

About

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors