Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current

Osterrieder, Wolfgang; Brum, Gustavo; Hescheler, Jürgen; Trautwein, W.; Flockerzi, Veit; Hofmann, Franz

doi:10.1038/298576a0

Cited by 408 publications

(137 citation statements)

References 15 publications

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“…These results suggest that an alternative regulatory mechanism is engaged at high stimulus levels in parallel with phosphorylation of Ser1700. Based on the extensive evidence indicating that PKA signaling is responsible for β-adrenergic regulation of Ca V 1.2 (3,17,18,20,(33)(34)(35)(36)(37), it seems most likely that this alternative regulatory mechanism involves PKA phosphorylation of undetected sites in Ca V 1.2 channels or associated regulatory proteins. A recent genome-wide phosphoproteomic study (38) also detected Ser1700 as a major phosphorylation site on cardiac Ca V 1.2 channels in response to β-adrenergic stimulation.…”

Section: Phosphorylation Of Ser1700 and Thr1704 Is Required For Normamentioning

confidence: 99%

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Westenbroek

Scheuer

et al. 2013

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

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The undersigned authors wish to note, "The KefFC system of E. coli is maintained in an inactive state by the binding of glutathione (GSH) and is activated by the formation of GSH adducts (GSX), particularly those with bulky substituents. We described two crystal structures with density present in the ligand-binding domain that we interpreted as GSH and GSX. Recently, an independent, experienced crystallographer, who had viewed the structures from our study in a different context, made representations to us that cast doubt on position of the succinimido ring of GSX. We have further reviewed the density maps with the aid of an experienced crystallographer. As a consequence, we believe it is important to draw this altered interpretation of the crystal structures to the attention of readers. In both structures, the density for the backbone of GSH is clear and allows unequivocal assignment of the position of the tripeptide. In PDB coordinate set 3L9X, the density for the succinimido ring is very weak, making interpretation very speculative and the assignment rests on the identity of the ligand added to the crystallization mixture, for which there are two diastereomers in the solutiona possibility that provides some basis for weakening the density. However, in 3L9W there are two anomalies that affect the interpretation of the bound ligand. First, there is no density for the carbon atom attached to the sulfur of GSH and second, there is extra density adjacent to the position of sulfur that could be modelled as a constrained succinimido ring. However, this density could also be water or any other molecule that is trapped in the structure. Thus, while there is good evidence for the peptide, the evidence that it is in the GSH form is uncertain."There are no new data on either the structures or on the gating mechanism. However, we believe that we should be cautious in interpreting the structural data and that the field in general should be made aware of the alternative views of the electron density data. Note that the mutagenesis and spectroscopic data that were presented in the original manuscript are not affected by this alternative interpretation." Tarmo P. The authors note that the following grant should be added to the Acknowledgments: "NIH Grant AG002132." The authors note "The method used for exogenous expression of Ca V 1.2 channels in ref. 32 was incorrectly described as 'viral transduction' in the text. In fact, Yang et al. created transgenic mice with inducible, cardiomyocyte-specific expression of exogenous Ca V 1.2 channels regulated by a tetracycline-inducible promoter. When crossed with a transgenic mouse line expressing doxycycline-regulated reverse transcriptional activator under control of the α-myosin heavy chain protomer, the resulting double transgenic offspring expressed exogenous Ca V 1.2 channels in their cardiac myocytes after treatment with doxycycline. The authors regret the error in describing these methods."www.pnas.org/cgi

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Section: Phosphorylation Of Ser1700 and Thr1704 Is Required For Normamentioning

confidence: 99%

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Westenbroek

Scheuer

et al. 2013

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

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“…cAMP functions mainly through activating cAMP-dependent protein kinase A (PKA), Epacs (exchange proteins directly activated by cAMP) [7,8] and cyclic nucleotide-gated ion channels [9,10]. A large number of PKA physiological substrates have been identified [11].…”

Section: Introductionmentioning

confidence: 99%

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

Wang

Zhou

et al. 2008

Cell Res

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cAMP and protein kinase A (PKA) are widely known as signaling molecules that are important for the induction of adipogenesis. Here we show that a strong increase in the amount of cAMP inhibits the adipogenesis of 3T3-L1 fibroblast cells. Stimulation of PKA activity suppresses adipogenesis and, in contrast, inhibition of PKA activity markedly accelerates the adipogenic process. As adipogenesis progresses, there is a significant increase in the expression level of PKA regulatory subunits and a corresponding decrease in PKA activity. Moreover, treatment of 3T3-L1 cells with epidermal growth factor (EGF) stimulates PKA activity and blocks adipogenesis. Inhibition of PKA activity abolishes this suppressive effect of EGF on adipogenesis. Moreover, activation of PKA induces serine/threonine phosphorylation, reduces tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and the association between PKA and IRS-1. Taken together, our study demonstrates that PKA has a pivotal role in the suppression of adipogenesis. cAMP at high concentrations can suppress adipogenesis through PKA activation. These findings could be important and useful for understanding the mechanisms of adipogenesis and the relevant physiological events.

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“…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). 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).…”

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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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Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current

Cited by 408 publications

References 15 publications

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

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

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Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current

Cited by 408 publications

References 15 publications

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

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

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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