Primary Structure and Function of an A Kinase Anchoring Protein Associated with Calcium Channels

Gray, Peter C.; Johnson, Barry D.; Westenbroek, Ruth E.; Hays, Lara G.; Yates, John R.; Scheuer, Todd; Catterall, William A.; Murphy, Brian J.

doi:10.1016/s0896-6273(00)80482-1

Cited by 177 publications

(171 citation statements)

References 40 publications

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“…We provide a direct validation of the negative feedback model suggested by such a molecular organization and prove that it applies to subsarcolemmal cAMP dynamics. Dodge et al (50) only found a modest PDE activity associated with AKAP15/18, the AKAP thought to associate with L-type Ca 2ϩ channels at the membrane (62,63). This fits well with the fact that limited cAMP increases induced by ISO fully activate I Ca,L , and suggests that the feedback loop identified here is essentially useful to prevent broadcast of cAMP outside of microdomains where it is needed (8,14).…”

Section: Discussionsupporting

confidence: 74%

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Rochais

Vandecasteele

Lefebvre

et al. 2004

Journal of Biological Chemistry

131

141

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Intracardiac cAMP levels are modulated by hormones and neuromediators with specific effects on contractility and metabolism. To understand how the same second messenger conveys different information, mutants of the rat olfactory cyclic nucleotide-gated (CNG) channel ␣-subunit CNGA2, encoded into adenoviruses, were used to monitor cAMP in adult rat ventricular myocytes. CNGA2 was not found in native myocytes but was strongly expressed in infected cells. In whole cell patchclamp experiments, the forskolin analogue L-858051 (L-85) elicited a non-selective, Mg 2؉ -sensitive current observed only in infected cells, which was thus identified as the CNG current (I CNG ). The ␤-adrenergic agonist isoprenaline (ISO) also activated I CNG , although the maximal efficiency was Ϸ5 times lower than with L-85. However, ISO and L-85 exerted a similar maximal increase of the L-type Ca 2؉ current. The use of a CNGA2 mutant with a higher sensitivity for cAMP indicated that this difference is caused by the activation of a localized fraction of CNG channels by ISO. cAMP-dependent protein kinase (PKA) blockade with H89 or PKI, or phosphodiesterase (PDE) inhibition with IBMX, dramatically potentiated ISO-and L-85-stimulated I CNG . A similar potentiation of ␤-adrenergic stimulation occurred when PDE4 was blocked, whereas PDE3 inhibition had a smaller effect (by 2-fold). ISO and L-85 increased total PDE3 and PDE4 activities in cardiomyocytes, although this effect was insensitive to H89. However, in the presence of IBMX, H89 had no effect on ISO stimulation of I CNG . This study demonstrates that subsarcolemmal cAMP levels are dynamically regulated by a negative feedback involving PKA stimulation of subsarcolemmal cAMP-PDE.Recent evidence indicates that multimolecular signaling complexes between cell surface receptors and intracellular targets are essential for the speed and specificity of signal transduction events (1, 2, 3). However, how such modules maintain specificity when small diffusible molecules are generated during the signaling cascade is difficult to investigate. This question is particularly relevant for cAMP in the heart, where this cyclic nucleotide second messenger exerts diverse effects in response to a number of different neuromediators and hormones. For instance, the ␤-adrenergic agonist isoprenaline (ISO), 1 prostaglandin E 1 (PGE 1 ), and glucagon-like peptide 1 (GLP-1) elevate intracardiac cAMP levels with different effects on contractility; ISO augments the force of contraction, PGE 1 does not, and GLP-1 exerts a negative inotropic effect (4, 5). In order to explain these results, subcellular compartmentation of cAMP was proposed more than 20 years ago (6).Localized cAMP signals may be generated by the interplay between discrete production sites and restricted diffusion within the cytoplasm. In addition to specialized membrane structures that may circumvent cAMP spreading (6, 7), degradation of cAMP into 5Ј-AMP by cyclic nucleotide phosphodiesterases (PDEs) appears critical for the formation of dynamic microdomain...

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Section: Discussionsupporting

confidence: 74%

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Rochais

Vandecasteele

Lefebvre

et al. 2004

Journal of Biological Chemistry

131

141

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“…The resulting antibody was affinity-purified on peptide columns as described (45), and specificity of the antibody was confirmed by immunoblotting. Anti-AKAP15 antibodies and RII-biotin protein were prepared as described (39). Anti-RII␣ antibody against the type II␣ regulatory subunit of PKA was kindly provided by G. Stanley McKnight (University of Washington).…”

Section: Methodsmentioning

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.

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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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“…A candidate for this is the receptor-activated cAMP-dependent protein-kinase (PKA) cascade. It has been shown that activation of PKA by stimulation with acetylcholine increases ADP-ribosyl cyclase activity in chromaffin cells [31], facilitates CD38 expression in Jurkat T cells [32] and enhances L-type VACC activity targeted by the PKA-anchoring protein [33].…”

Section: Scheme 1 Models For Reciprocal Interactions Between Ryrs Andmentioning

confidence: 99%

cADP-ribose potentiates cytosolic Ca2+ elevation and Ca2+ entry via L-type voltage-activated Ca2+ channels in NG108-15 neuronal cells

Hashii

Minabe

Higashida

2000

Biochemical Journal

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The effects of cADP-ribose (cADPR), a metabolite of β-NAD + , on the elevation of cytoplasmic free Ca# + concentration ([Ca# + ] i ) and Ca# + influx through voltage-activated Ca# + channels (VACCs) were studied in NG108-15 neuroblastomaiglioma hybrid cells. NG108-15 cells were pre-loaded with fura-2 and whole-cell patch-clamped. Application of cADPR through patch pipettes did not by itself trigger any [Ca# + ] i rise at the resting membrane potential. A rise in [Ca# + ] i was evoked upon sustained membrane depolarization, and was significantly larger in cADPR-infused cells than in non-infused cells. This potentiation in the [Ca# + ] i elevation was reproduced by infusion of β-NAD + , and was blocked by 8-bromo-cADPR and antagonized by external application of ryanodine or by pretreatment of cells with FK506. Nicotinamide inhibited β-NAD + -induced, but not cADPR-elicited, potentiation. [Ca# + ] i increases or Ca# + influx,

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Primary Structure and Function of an A Kinase Anchoring Protein Associated with Calcium Channels

Cited by 177 publications

References 40 publications

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

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

cADP-ribose potentiates cytosolic Ca2+ elevation and Ca2+ entry via L-type voltage-activated Ca2+ channels in NG108-15 neuronal cells

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Primary Structure and Function of an A Kinase Anchoring Protein Associated with Calcium Channels

Cited by 177 publications

References 40 publications

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

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

cADP-ribose potentiates cytosolic Ca2+ elevation and Ca2+ entry via L-type voltage-activated Ca2+ channels in NG108-15 neuronal cells

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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