Regulation of calcium channel expression in neonatal myocytes by catecholamines.

Mäki, Tiina; Gruver, E. James; Davidoff, Amy J.; Izzo, Nicholas J.; Toupin, Darlene; Colucci, Wilson S.; Marks, Andrew R.; Marsh, James D.

doi:10.1172/jci118462

Cited by 81 publications

(48 citation statements)

References 36 publications

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“…As has been reported, ISO treatment of neonatal cardiomyocytes increased expression of 1c which resulted in a functional increase in the density of ICa. 25,26 We suggest that in our study, the increased expression of INa and ICa contributes to the measured increase in the upstroke velocity of the AP.…”

Section: Ion Channelssupporting

confidence: 49%

Beta-, Not Alpha-Adrenergic Stimulation Enhances Conduction Velocity in Cultures of Neonatal Cardiomyocytes

Boer

Rijen

Heyden

et al. 2007

Circ J

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n the mature circulatory system, -adrenergic stimulation predominantly affects vessel diameter whereas 1-adrenergic stimulation determines the adaptation of heart rate and contractility to changing demands. In the immature stages of heart development, postnatal maturation coincides with in-growth of sympathetic neurons, elevated levels of released catecholamines and enhanced expression of -adrenoreceptors. 1 Shortly after birth, hyperplasia of the cardiomyocytes ceases and is followed by hypertrophic growth and maturation. 2 During maturation, cardiac rhythm becomes slower, while conduction velocity (CV) of the electrical impulse, which is initially slow, 3 increases. Several factors contribute to cell-to-cell propagation of the cardiac electrical impulse, which is enabled by specialized membrane structures named gap junctions. Gap junctions are agglomerates of intercellular channels composed of hexagonally arranged connexin (Cx) proteins. The Circulation Journal Vol.71, June 2007Cxs form a large family of transmembrane proteins, and are expressed in virtually all vertebrate cells. 4 Three isoforms, Cx40, -43 and -45, are expressed by mammalian cardiomyocytes. Expression of the isoforms is not uniform within cardiac tissue, differs between the species and is subject to developmental changes. [5][6][7][8] Cx43, as expressed between all working myocardial cells, is predominant. Intercellular gap junctional communication is determined by the number and distribution of expressed gap junction channels (n), the open probability of each channel (Po) and the single-channel conductance ( j). Po and j differ between gap junction isoforms and are subject to post-translational modulation (eg, by phosphorylation). 9 Propagation further depends on the level of expression of the protein subunits that constitute the ion channels responsible for the electrical make-up of the action potential (AP). In adult hearts, sodium channel availability in particular determines the upstroke velocity of the AP. In immature hearts, availability of the L-type calcium channel is most important in this respect. The higher the upstroke velocity, the faster a depolarized myocyte is able to trigger adjacent myocytes. Within the syncytium of all connected cardiomyocytes, changes in upstroke velocity thereby reflect on CV.A third factor that affects propagation is the geometry of the tissue. Differences in cell size and shape affect the conCirc J 2007; 71: 973 -981 (Received September 11, 2006; revised manuscript received March 6, 2007; accepted March 19, 2007 Background During both cardiac maturation and myopathy, elevated levels of circulating catecholamines coincide with alterations in impulse propagation. An in vitro model of cultured cardiomyocytes was used to study the effects of adrenergic stimulation on the conduction characteristics of immature heart cells. Methods and ResultsNeonatal rat cardiomyocytes were cultured on preparations designed to measure conduction velocity (CV). CV was measured on the same preparation twice at t=0 and at t...

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Section: Ion Channelssupporting

confidence: 49%

Beta-, Not Alpha-Adrenergic Stimulation Enhances Conduction Velocity in Cultures of Neonatal Cardiomyocytes

Boer

Rijen

Heyden

et al. 2007

Circ J

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“…␤-adrenoceptors via increased intracellular cAMP content (18). Sympathetic innervation of newborn rat hearts increases the transient outward current (I to ) and I K1 density (17).…”

Section: Discussionmentioning

confidence: 99%

Effects of sustained β-adrenergic stimulation on ionic currents of cultured adult guinea pig cardiomyocytes

Zhang

Wang

Nattel

2002

American Journal of Physiology-Heart and Circulatory Physiology

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Short-term stimulation of β-receptors is known to affect cardiac ion channels; however, the impact of longer-term stimulation on intrinsic channel function is poorly understood. To evaluate this, cultured guinea pig ventricular myocytes were exposed to isoproterenol (10 nM), vehicle, or isoproterenol plus propranolol (1 μM) for 48 h. Sustained exposure to isoproterenol decreased the density of the inward rectifier ( I K1), slow delayed rectifier ( I Ks), and L-type Ca2+( I Ca L) currents, effects that were fully prevented by propranolol. Changes in K+ currents were prevented by the β1-selective antagonist CGP-20712A, unaffected by the β2-antagonist ICI-118,551, and mimicked by the membrane-permeable cAMP analog 8-bromo-cAMP. Isoproterenol did not alter the current-voltage relationship of the K+currents but increased the density of T-type Ca2+ current ( I Ca T) and thereby increased the proportion of the total Ca2+ current at more negative potentials. We conclude that sustained exposure to isoproterenol reduces I K1, I Ks, and I Ca L density and increases the density of I Ca T. The direct ionic current remodeling effects of sustained β-adrenoceptor stimulation resemble changes reported with heart failure and may be important in arrhythmogenic ionic remodeling.

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“…In cardiac myocytes, incubation in high Ca 2ϩ increased both transcription of ␣ 1C channels and DHP binding (Davidoff et al, 1997). In contrast, exposure to phenylephrine, an ␣ 1 adrenergic agonist with signal transduced as cytosolic Ca 2ϩ elevation via receptor-operated calcium channels, decreased ␣ 1C transcripts and L-type calcium currents (Maki et al, 1996). Isoproterenol and 8-bromocAMP increased Ca 2ϩ channel mRNA and peak calcium current (Maki et al, 1996).…”

Section: Promoters and Expression Regulationmentioning

confidence: 99%

Structure-Functional Diversity of Human L-Type Ca²⁺Channel: Perspectives for New Pharmacological Targets: Figure 1

Abernethy¹,

Soldatov²

2002

J Pharmacol Exp Ther

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The L-type Ca 2ϩ channels mediate depolarization-induced influx of Ca 2ϩ into a wide variety of cells and thus play a central role in triggering cardiac and smooth muscle contraction. Because of this role, clinically important classes of 1,4-dihydropyridine, phenylalkylamine, and benzothiazepine Ca 2ϩ channel blockers were developed as powerful medicines to treat hypertension and angina pectoris. Molecular cloning studies revealed that the channel is subject to extensive structure-functional variability due to alternative splicing. In this review, we will focus on a potentially important role of genetically driven variability of Ca 2ϩ channels in expression regulation and mutations, Ca 2ϩ -induced inactivation, and modulation of sensitivity to Ca 2ϩ channel blockers with the perspective for new pharmacological targets.The L-type Ca 2ϩ channel is a ubiquitously expressed voltage-gated ion channel supporting inward current of Ca 2ϩ ions that play a central role as an intracellular second messenger in many processes ranging from gene expression to cardiac and smooth muscle contraction. A number of L-type Ca 2ϩ channel blockers have been developed for the treatment of cardiovascular disorders. 1,4-Dihydropyridines, which have proven to be the most potent inhibitors of the channel, were used for its biochemical identification in rabbit skeletal muscle T-tubules as a protein complex composed of the poreforming ␣ 1S subunit and auxiliary ␣ 2 ␦, ␤, and ␥ subunits. Two dihydropyridine-sensitive genetic variants of ␣ 1S have been identified and cloned from heart (␣ 1C ) and pancreatic beta cells (␣ 1D ), with the cardiac ␣ 1C isoform being expressed in the vast majority of eukaryotic cells. Activity of the ␣ 1C channel is highly regulated by membrane potential, other calcium channel auxiliary subunits (␣ 2 ␦, ␤), as well as by feedback dependence on permeating Ca 2ϩ , which is mediated by calmodulin. The genetic regulation of the ␣ 1C Ca 2ϩ channel subunit occurs through species-specific variability and largely tissue-specific alternative splicing. In this review, we briefly discuss genomic organization of the ␣ 1C subunit gene and then focus attention on alternative splicing that generates functionally distinct Ca 2ϩ channel isoforms as potentially new pharmacological targets.

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Regulation of calcium channel expression in neonatal myocytes by catecholamines.

Cited by 81 publications

References 36 publications

Beta-, Not Alpha-Adrenergic Stimulation Enhances Conduction Velocity in Cultures of Neonatal Cardiomyocytes

Beta-, Not Alpha-Adrenergic Stimulation Enhances Conduction Velocity in Cultures of Neonatal Cardiomyocytes

Effects of sustained β-adrenergic stimulation on ionic currents of cultured adult guinea pig cardiomyocytes

Structure-Functional Diversity of Human L-Type Ca²⁺Channel: Perspectives for New Pharmacological Targets: Figure 1

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Regulation of calcium channel expression in neonatal myocytes by catecholamines.

Cited by 81 publications

References 36 publications

Beta-, Not Alpha-Adrenergic Stimulation Enhances Conduction Velocity in Cultures of Neonatal Cardiomyocytes

Beta-, Not Alpha-Adrenergic Stimulation Enhances Conduction Velocity in Cultures of Neonatal Cardiomyocytes

Effects of sustained β-adrenergic stimulation on ionic currents of cultured adult guinea pig cardiomyocytes

Structure-Functional Diversity of Human L-Type Ca2+Channel: Perspectives for New Pharmacological Targets: Figure 1

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Structure-Functional Diversity of Human L-Type Ca²⁺Channel: Perspectives for New Pharmacological Targets: Figure 1