Cardiac-specific Overexpression of the α1 Subunit of the L-type Voltage-dependent Ca2+ Channel in Transgenic Mice

Muth, James N.; Yamaguchi, Hiroshi; Mikala, Gábor; Grupp, Ingrid L.; Lewis, William; Cheng, Heping; Song, Long‐Sheng; Lakatta, Edward G.; Váradi, Gyula; Schwartz, Arnold

doi:10.1074/jbc.274.31.21503

Cited by 66 publications

(62 citation statements)

References 24 publications

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“…Recent findings by Carrion and co-workers (44) demonstrated that even slight elevations of Ca 2ϩ can stimulate the DNA-binding transcriptional regulator protein DREAM, thus inducing the expression of several growth genes. This pathway was considered in a transgenic mouse model with targeted overexpression of the ␣ 1 subunit of the L-type Ca 2ϩ channel, which exhibited a mild cardiac hypertrophy (45). At present, however, we can only speculate which Ca 2ϩ -activated pathway may lead to the hypertrophy observed in the present model.…”

Section: Discussionmentioning

confidence: 92%

Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1

Kirchhefer¹,

Neumann²,

Baba³

et al. 2001

Journal of Biological Chemistry

101

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Triadin 1 is a major transmembrane protein in cardiac junctional sarcoplasmic reticulum (SR), which forms a quaternary complex with the ryanodine receptor (Ca 2؉ release channel), junctin, and calsequestrin. To better understand the role of triadin 1 in excitation-contraction coupling in the heart, we generated transgenic mice with targeted overexpression of triadin 1 to mouse atrium and ventricle, employing the ␣-myosin heavy chain promoter to drive protein expression. The protein was overexpressed 5-fold in mouse ventricles, and overexpression was accompanied by cardiac hypertrophy. The levels of two other junctional SR proteins, the ryanodine receptor and junctin, were reduced by 55% and 73%, respectively, in association with triadin 1 overexpression, whereas the levels of calsequestrin, the Ca 2؉ -binding protein of junctional SR, and of phospholamban and SERCA2a, Ca 2؉ -handling proteins of the free SR, were unchanged. Cardiac myocytes from triadin 1-overexpressing mice exhibited depressed contractility; Ca 2؉ transients decayed at a slower rate, and cell shortening and relengthening were diminished. The extent of depression of cell shortening of triadin 1-overexpressing cardiomyocytes was rate-dependent, being more depressed under low stimulation frequencies (0.5 Hz), but reaching comparable levels at higher frequencies of stimulation (5 Hz). Spontaneously beating, isolated work-performing heart preparations overexpressing triadin 1 also relaxed at a slower rate than control hearts, and failed to adapt to increased afterload appropriately. The fast time inactivation constant, 1 , of the L-type Ca 2؉ channel was prolonged in transgenic cardiomyocytes. Our results provide evidence for the coordinated regulation of junctional SR protein expression in heart independent of free SR protein expression, and furthermore suggest an important role for triadin 1 in regulating the contractile properties of the heart during excitation-contraction coupling.

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Section: Discussionmentioning

confidence: 92%

Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1

Kirchhefer¹,

Neumann²,

Baba³

et al. 2001

Journal of Biological Chemistry

101

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“…Overexpression of the a1-subunit of the L-type Ca 21 channel in transgenic mouse ventricles resulted in significantly reduced inotropic and lusitropic responses to isoproterenol and forskolin [76]. Isoproterenol and forskolin stimulation of Ca 21 current was markedly depressed in transgenic cardiomyocytes, isoproterenol-stimulated adenylate cyclase activity was absent and NaF and forskolin responses were reduced.…”

Section: -T Y P E V O L T a G E D E P E N D E N T C A R D Imentioning

confidence: 97%

Ca²⁺ signalling and muscle disease

MacLennan

2000

European Journal of Biochemistry

221

155

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Transient elevations of intracellular Ca2+ play a signalling role in such complex cellular functions as contraction, secretion, fertilization, proliferation, metabolism, heartbeat and memory. However, prolonged elevation of Ca2+ above about 10 µm is deleterious to a cell and can activate apoptosis. In muscle, there is a narrow window of Ca2+ dysregulation in which abnormalities in Ca2+ regulatory proteins can lead to disease, rather than apoptosis. Key proteins in the regulation of muscle Ca2+ are the voltage‐dependent, dihydropyridine‐sensitive, l‐type Ca2+ channels located in the transverse tubule and Ca2+ release channels in the junctional terminal cisternae of the sarcoplasmic reticulum. Abnormalities in these proteins play a key role in malignant hyperthermia (MH), a toxic response to anesthetics, and in central core disease (CCD), a muscle myopathy. Sarco(endo)plasmic reticulum Ca2+ ATPases (SERCAs) return sarcoplasmic Ca2+ to the lumen of the sarcoplasmic reticulum. Loss of SERCA1a Ca2+ pump function is one cause of exercise‐induced impairment of the relaxation of skeletal muscle, in Brody disease. Phospholamban expressed in cardiac muscle and sarcolipin expressed in skeletal muscle regulate SERCA activity. Studies with knockout and transgenic mice show that gain of inhibitory function of phospholamban alters cardiac contractility and could be a causal feature in some cardiomyopathies. Calsequestrin, calreticulin, and a series of other acidic, lumenal, Ca2+ binding proteins provide a buffer for Ca2+ stored in the sarcoplasmic reticulum. Overexpression of cardiac calsequestrin leads to cardiomyopathy and ablation of calreticulin alters cardiac development.

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“…Whereas numerous studies described cloning of Ca 2ϩ channel subunits and Ca 2ϩ channel composition in the human, guinea pig, and rat heart (5,7,25,29,39,40,41) the molecular "make-up" of the mouse cardiac LTCC is much less defined, although several mouse lines have been created with Ca 2ϩ channel subunit transgenes as preclinical models for heart diseases (22,23,24,42,43).…”

Section: Discussionmentioning

confidence: 99%

Diversity and Developmental Expression of L-type Calcium Channel β2 Proteins and Their Influence on Calcium Current in Murine Heart

Link

Meissner

Held³

et al. 2009

Journal of Biological Chemistry

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By now, little is known on L-type calcium channel (LTCC) subunits expressed in mouse heart. We show that CaV␤2 proteins are the major CaV␤ components of the LTCC in embryonic and adult mouse heart, but that in embryonic heart CaV␤3 proteins are also detectable. At least two CaV␤2 variants of ϳ68 and ϳ72 kDa are expressed. To identify the underlying CaV␤2 variants, cDNA libraries were constructed from poly(A) ؉ RNA isolated from hearts of 7-day-old and adult mice. Screening identified 60 independent CaV␤2 cDNA clones coding for four types of CaV␤2 proteins only differing in their 5 sequences. CaV␤2-N1, -N4, and -N5 but not -N3 were identified in isolated cardiomyocytes by RT-PCR and were sufficient to reconstitute the CaV␤2 protein pattern in vitro. Significant L-type Ca 2؉ currents (I Ca ) were recorded in HEK293 cells after co-expression of CaV1.2 and CaV␤2. Current kinetics were determined by the type of CaV␤2 protein, with the ϳ72-kDa CaV␤2a-N1 shifting the activation of I Ca significantly to depolarizing potentials compared with the other CaV␤2 variants. Inactivation of I Ca was accelerated by CaV␤2a-N1 and -N4, which also lead to slower activation compared with CaV␤2a-N3 and -N5. In summary, this study reveals the molecular LTCC composition in mouse heart and indicates that expression of various CaV␤2 proteins may be used to adapt the properties of LTCCs to changing myocardial requirements during development and that CaV␤2a-N1-induced changes of I Ca kinetics might be essential in embryonic heart.

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Cardiac-specific Overexpression of the α1 Subunit of the L-type Voltage-dependent Ca2+ Channel in Transgenic Mice

Cited by 66 publications

References 24 publications

Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1

Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1

Ca²⁺ signalling and muscle disease

Diversity and Developmental Expression of L-type Calcium Channel β2 Proteins and Their Influence on Calcium Current in Murine Heart

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Cardiac-specific Overexpression of the α1 Subunit of the L-type Voltage-dependent Ca2+ Channel in Transgenic Mice

Cited by 66 publications

References 24 publications

Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1

Cardiac Hypertrophy and Impaired Relaxation in Transgenic Mice Overexpressing Triadin 1

Ca2+ signalling and muscle disease

Diversity and Developmental Expression of L-type Calcium Channel β2 Proteins and Their Influence on Calcium Current in Murine Heart

Contact Info

Product

Resources

About

Ca²⁺ signalling and muscle disease