Localization of <i>beta</i> adrenergic receptors, and effects of noradrenaline and cyclic nucleotides on action potentials, ionic currents and tension in mammalian cardiac muscle

Réuter, H.

doi:10.1113/jphysiol.1974.sp010716

Cited by 407 publications

(137 citation statements)

References 55 publications

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“…(i) The Ca2+ in pool A turns over rapidly, and its release to the cell could be triggered by the influx of extracellular Ca2+ and (ii) the size of pool A, especially when measured after isoproterenol treatment, is adequate to fully saturate the myofibrils with Ca2+ (25). Additional measurements are required to determine whether the effect of isoproterenol is due to actual enhancement in the steady-state size of pool A or to stimulation of the rate of turnover of pool A. Enhancement by isoproterenol ofinflux ofextracellular Ca2+ during depolarization has previously been reported (26). …”

Section: Methodsmentioning

confidence: 99%

Measurement of rapidly exchangeable cellular calcium in the perfused beating rat heart.

Hunter¹,

Haworth²,

Berkoff³

1981

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

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Although Ca2+ has long been known to play a vital role in excitation-contraction coupling in the heart, investigation of the details of this role has been hampered by the experimental difficulty of measuring Ca2+ movements through the different compartments ofthe cell. A major problem has been to distinguish the relatively small amount of rapidly exchangeable cellular Ca2+ from the large amount ofvascular and interstitial Ca2+. We report here a method that overcomes this problem. Rat Excitation ofthe heart induces an increase in cellular free Ca2", which then triggers myocardial contraction (1). The immediate origin of this Ca2" has been the subject of much controversy (for review, see refs. 2-5). Much of it may come from cellular stores. However, attempts to measure myocardial cellular Ca2" have met with limited success. Ca2' influx during excitation of the myocardial cell has been demonstrated electrophysiologically (6-8), although the extent of this influx is still in dispute.With the aid of aequorin, a Ca2+-sensitive fluorescent probe, a beat-to-beat fluctuation ofcytoplasmic levels offree Ca2+ has been observed in the frog heart (1). However, the interpretation ofexperiments designed to measure Ca2+ fluxes by using 'Ca2+ has been equivocal. Experiments with heart tissue have shown beat-dependent 'Ca2+ uptake (9-14) but of a magnitude far greater than found in cultures of beating neonatal cells (15). In all cases, a major problem has been that the cellular Ca2+ represents such a small fraction of the total Ca2+ in the tissue that it is almost impossible to detect. Furthermore, cellular Ca2+ fluxes occur on a time scale similar to that of vascular and interstitial washout time, so that although kinetic analysis of 'Ca2+ washout from the whole heart shows many pools (16, 17), the pool of interest is still difficult to distinguish from the extracellular pools. We have circumvented this problem by using the well-known fact that active processes have a much higher Q1o than simple diffusion. Thus, by cooling the heart after labeling with perfusate containing 'Ca2 , the cellular '5Ca2+ becomes trapped. The high background 'Caa2+ from vascular and interstitial spaces is then removed by perfusion at 6°C, so that cellular Ca2+ can readily be detected be releasing it with a second warm perfusion. METHODSLabeling of Heart with 'Ca"+. Retired female breeder rats (Sprague-Dawley) were anesthetized by intraperitoneal injection of thiamylal (100 mg/kg). The heart was excised, and cannulas were placed in the aorta and pulmonary vein. Incisions were made in the pulmonary artery and the right atria to allow adequate flow. The basal perfusate was 118 mM NaCV25 mM NaHCOV4.7 mM KCV1.2 mM KH2POd1.2 mM MgSO411 mM glucose/2.5 mM CaCl2, pH 7.4. It was bubbled with 95% 02/5% Co2 and warmed to 37°C. The heart was perfused for 10 sec through the pulmonary vein cannula to wash out any air bubbles. Then it was perfused for the remainder ofthe perfusion period through the aorta. The height ofthe reservoir was 65 cm above the hea...

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Section: Methodsmentioning

confidence: 99%

Measurement of rapidly exchangeable cellular calcium in the perfused beating rat heart.

Hunter¹,

Haworth²,

Berkoff³

1981

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

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“…Whereas the majority of Ca 2ϩ channel ␣ 1 subunits isolated from cardiac muscle are truncated (11,14,15), the cleaved distal C terminus remains associated with the truncated ␣ 1 subunit of Ca V 1.2 after proteolytic processing, and peptides derived from it can regulate channel activity (16,17). Ca V 1.2 channels can be modulated by a variety of receptormediated processes, including stimulation through activation of the ␤-adrenergic receptor͞cAMP signaling pathway (4,(18)(19)(20)(21). Activation of ␤-adrenergic receptors increases cardiac L-type Ca 2ϩ currents through cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of the Ca V 1.2 channel protein and͞or associated proteins (22,23).…”

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confidence: 99%

β-Adrenergic regulation requires direct anchoring of PKA to cardiac Ca _V 1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15

Hulme

Lin

Westenbroek

et al. 2003

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

213

235

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.2 channels and PKA in the transverse tubules of isolated ventricular myocytes. Site-directed mutagenesis studies reveal that AKAP15 directly interacts with the distal C terminus of the cardiac Ca V1.2 channel via a leucine zipper-like motif. Disruption of PKA anchoring to Ca V1.2 channels via AKAP15 using competing peptides markedly inhibits the ␤-adrenergic regulation of CaV1.2 channels via the PKA pathway in ventricular myocytes. These results identify a conserved leucine zipper motif in the C terminus of the Ca V1 family of Ca 2؉ channels that directly anchors an AKAP15-PKA signaling complex to ensure rapid and efficient regulation of L-type Ca 2؉ currents in response to ␤-adrenergic stimulation and local increases in cAMP.V oltage-gated L-type calcium (Ca 2ϩ ) channels play a pivotal role in the regulation of a wide range of cellular processes, including membrane excitability, Ca 2ϩ homeostasis, protein phosphorylation, and gene regulation. In cardiac myocytes, Ca 2ϩ influx through Ca V 1.2 channels contributes to the plateau phase of the cardiac action potential and is responsible for initiating excitation-contraction coupling (1-3). Voltage-gated L-type Ca 2ϩ channels are multisubunit complexes composed of a poreforming ␣ 1 subunit and auxiliary ␤ and ␣ 2 ␦ subunits (4). In cardiac muscle, a distinct ␣ 1 subunit (␣ 1 1.2a) (5, 6), an ␣ 2 ␦ subunit (7), and several isoforms of ␤ subunits [␤ 1b and ␤ 2a-d (8-11)] have been identified and implicated to form the Ca V 1.2 channel. As for the skeletal muscle Ca V 1.1 channel (12, 13), two size forms of the ␣ 1 1.2a subunit of Ca V 1.2 channels, Ϸ240 and 210 kDa, are present in cardiac muscle and differ by truncation at the C terminus (14). Whereas the majority of Ca 2ϩ channel ␣ 1 subunits isolated from cardiac muscle are truncated (11,14,15), the cleaved distal C terminus remains associated with the truncated ␣ 1 subunit of Ca V 1.2 after proteolytic processing, and peptides derived from it can regulate channel activity (16,17). Ca V 1.2 channels can be modulated by a variety of receptormediated processes, including stimulation through activation of the ␤-adrenergic receptor͞cAMP signaling pathway (4, 18-21). Activation of ␤-adrenergic receptors increases cardiac L-type Ca 2ϩ currents through cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of the Ca V 1.2 channel protein and͞or associated proteins (22, 23). As for skeletal muscle Ca v 1.1 channels (24, 25), both the ␣ 1 and ␤ subunits of Ca V 1.2 channels are substrates for phosphorylation by PKA (14,(26)(27)(28). PKA phosphorylates only the full-length form of the ␣ 1 subunit, on a single site containing serine 1928 in the C-terminal domain (14,26). In contrast, the C-terminal truncated ␣ 1 subunit is not a substrate for phosphorylation by PKA in vitro (14,26). Ca V 1.2 channels consisting of only ␣ 1 subunits can be regulated by PKA, implicating phosphorylation of serine 1928 in channel regulation (29, 30). Mutation of serine 1928 to alanine prevents PKAdependent phosphorylation and the low l...

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“…Adrenergic up-regulation of the cardiac I Ca is an extensively studied physiological phenomenon that was recognized in the seventies (35) to be regulated by cAMP. Since then evidence has been published that ␤-adrenergic stimulation requires a PKAmediated phosphorylation step (3, 4, 7, 20, 36 -39).…”

Section: Discussionmentioning

confidence: 99%

Deletion of the C-terminal Phosphorylation Sites in the Cardiac β-Subunit Does Not Affect the Basic β-Adrenergic Response of the Heart and the Cav1.2 Channel

Brandmayr

Poomvanicha

Domes

et al. 2012

Journal of Biological Chemistry

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Background: ␤-Adrenergic receptors stimulate cardiac I Ca via PKA-dependent phosphorylation. Results: Deletion of the C-terminal phosphorylation sites in the ␤ 2 gene did not affect isoproterenol-stimulated I Ca . Conclusion: Phosphorylation of the C terminus of the ␤ 2 subunit in vivo does not contribute to ␤-adrenergic regulation of I Ca . Significance: The PKA-dependent regulation of I Ca does not require the C terminus of the ␤ 2 subunit.

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Localization of beta adrenergic receptors, and effects of noradrenaline and cyclic nucleotides on action potentials, ionic currents and tension in mammalian cardiac muscle

Cited by 407 publications

References 55 publications

Measurement of rapidly exchangeable cellular calcium in the perfused beating rat heart.

Measurement of rapidly exchangeable cellular calcium in the perfused beating rat heart.

β-Adrenergic regulation requires direct anchoring of PKA to cardiac Ca _V 1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15

Deletion of the C-terminal Phosphorylation Sites in the Cardiac β-Subunit Does Not Affect the Basic β-Adrenergic Response of the Heart and the Cav1.2 Channel

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Localization of beta adrenergic receptors, and effects of noradrenaline and cyclic nucleotides on action potentials, ionic currents and tension in mammalian cardiac muscle

Cited by 407 publications

References 55 publications

Measurement of rapidly exchangeable cellular calcium in the perfused beating rat heart.

Measurement of rapidly exchangeable cellular calcium in the perfused beating rat heart.

β-Adrenergic regulation requires direct anchoring of PKA to cardiac Ca V 1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15

Deletion of the C-terminal Phosphorylation Sites in the Cardiac β-Subunit Does Not Affect the Basic β-Adrenergic Response of the Heart and the Cav1.2 Channel

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β-Adrenergic regulation requires direct anchoring of PKA to cardiac Ca _V 1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15