Targeting of Protein Kinase A by Muscle A Kinase-anchoring Protein (mAKAP) Regulates Phosphorylation and Function of the Skeletal Muscle Ryanodine Receptor

Ruehr, Mary L.; Russell, Mary A.; Ferguson, Donald G.; Bhat, Manjunatha B.; Ma, Jianjie; Damron, Derek S.; Scott, John D.; Bond, Meredith

doi:10.1074/jbc.m213279200

Cited by 60 publications

(56 citation statements)

References 56 publications

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“…Moreover, by expression of a mutant form of mAKAP lacking the PKA binding domain (mAKAP Del PKA BD), we showed that the ability of mAKAP to bind PKA was functionally relevant to mAKAP complex hypertrophic signaling. The PKA responsible for phosphorylation of mAKAP-associated RyR2 is presumably PKA bound to mAKAP Marx et al, 2000;Ruehr et al, 2003). While PKA can diffuse non-specifically towards its substrates, targeting by AKAPs increases the rate of the phosphorylation reaction and the efficiency of the signaling (Kapiloff, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…mAKAP is located at the nuclear envelope where it is tethered by the integral membrane protein nesprin-1␣ through the direct binding of spectrin repeats in each protein . Named for its ability to bind the type II PKA holoenzyme (Kapiloff et al, 1999;Zakhary et al, 2000), mAKAP also binds the cAMP-specific phosphodiesterase PDE4D3, the cardiac-specific type II ryanodine receptor (RyR2), and protein phosphatase 2A (Dodge et al, 2001;Dodge-Kafka et al, 2005;Kapiloff et al, 2001;Marx et al, 2000;Ruehr et al, 2003). Recently, we reported that the MAP kinases MEK5 and ERK5, the small GTPase Rap1, and the cAMP-activated Rap1 exchange factor Epac1 are also anchored by mAKAP (Dodge-Kafka et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…The ␤-adrenergic receptor stimulates adenylate cyclase and increases intracellular cAMP levels and, subsequently, PKA activity. mAKAP-bound PKA can phosphorylate associated RyR2 (Kapiloff, 2002;Marx et al, 2000;Ruehr et al, 2003), potentiating channel activity (Hain et al, 1995;. It is generally understood that RyR2 mediates Ca 2+ -induced Ca 2+ release from the sarcoplasmic reticulum during excitation-contraction coupling (Fill and Copello, 2002).…”

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confidence: 99%

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The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling

Paré

Bauman

McHenry

et al. 2005

Journal of Cell Science

116

160

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Maladaptive cardiac hypertrophy can progress to congestive heart failure, a leading cause of morbidity and mortality in the United States. A better understanding of the intracellular signal transduction network that controls myocyte cell growth may suggest new therapeutic directions. mAKAP is a scaffold protein that has recently been shown to coordinate signal transduction enzymes important for cytokine-induced cardiac hypertrophy. We now extend this observation and show mAKAP is important for adrenergic-mediated hypertrophy. One function of the mAKAP complex is to facilitate cAMPdependent protein kinase A-catalyzed phosphorylation of the ryanodine receptor Ca 2+ -release channel. Experiments utilizing inhibition of the ryanodine receptor, RNA interference of mAKAP expression and replacement of endogenous mAKAP with a mutant form that does not bind to protein kinase A demonstrate that the mAKAP complex contributes to pro-hypertrophic signaling. Further, we show that calcineurin A␤ ␤ associates with mAKAP and that the formation of the mAKAP complex is required for the full activation of the pro-hypertrophic transcription factor NFATc. These data reveal a novel function of the mAKAP complex involving the integration of cAMP and Ca 2+ signals that promote myocyte hypertrophy. Journal of Cell Science 5638 from the nuclear envelope, we showed that mAKAP was required for the induction of myocyte hypertrophy by this cytokine-regulated signaling pathway (Dodge-Kafka et al., 2005). We now report that mAKAP is important for the induction of myocyte hypertrophy by adrenergic receptor signaling. The ␤-adrenergic receptor stimulates adenylate cyclase and increases intracellular cAMP levels and, subsequently, PKA activity. mAKAP-bound PKA can phosphorylate associated RyR2 (Kapiloff, 2002;Marx et al., 2000;Ruehr et al., 2003), potentiating channel activity (Hain et al., 1995;. It is generally understood that RyR2 mediates Ca 2+ -induced Ca 2+ release from the sarcoplasmic reticulum during excitation-contraction coupling (Fill and Copello, 2002). We have found, however, a small pool of RyR2 associated with mAKAP at the nuclear envelope ). mAKAP-associated RyR2 might regulate the release of Ca 2+ from adjacent, peri-nuclear sarcoplasmic reticulum or the release of putative stores within the nuclear envelope (Abrenica and Gilchrist, 2000). We now present evidence that mAKAP is integral to the induction of ␤-adrenergic-stimulated hypertrophy by participating in the CaN-NFATc signaling pathway. We show further that mAKAP is also relevant to ␣-adrenergic signaling. In contrast to the ␤-adrenergic receptor, the ␣-adrenergic receptor activates phospholipase C and phosphatidyl inositol pathways, resulting in increased intracellular Ca 2+ levels and activation of MAP kinases (including MEK5 and ERK5) and CaN (Dorn and Force, 2005;Nicol et al., 2001). Given the ability of mAKAP to anchor ERK5, PKA, RyR2, and, as shown below, CaN, to the nuclear envelope, we propose that the mAKAP scaffold may serve as an integrator for hypertrophic signa...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling

Paré

Bauman

McHenry

et al. 2005

Journal of Cell Science

116

160

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“…A relation between RyR3 expression and resting cytosolic calcium levels has been demonstrated in 1B5 myotubes in culture and in murine fibers during early postnatal development (596). Since the expression of specific RyR isoforms does not seem to be directly relevant, the fiber type-related diversity in calcium release might be determined by other factors, such as 1) posttranslational modifications, as RyR is target for phosphorylation by PKA (668) and is affected by oxidative state (370); 2) interactions with other proteins including DHPR, calmodulin, FKBP-12, and calsequestrin; and 3) amount of calcium available in the terminal cisternae, as SR is maximally loaded in slow but not in fast fibers (see below). The DHPR, i.e., the L-type voltage-gated calcium channel which acts as a voltage sensor during E-C coupling, has been considered in the previous section (see sect.…”

Section: Calcium Release From Srmentioning

confidence: 99%

Fiber Types in Mammalian Skeletal Muscles

Schiaffino

Reggiani

2011

Physiological Reviews

2,313

2,465

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Mammalian skeletal muscle comprises different fiber types, whose identity is first established during embryonic development by intrinsic myogenic control mechanisms and is later modulated by neural and hormonal factors. The relative proportion of the different fiber types varies strikingly between species, and in humans shows significant variability between individuals. Myosin heavy chain isoforms, whose complete inventory and expression pattern are now available, provide a useful marker for fiber types, both for the four major forms present in trunk and limb muscles and the minor forms present in head and neck muscles. However, muscle fiber diversity involves all functional muscle cell compartments, including membrane excitation, excitation-contraction coupling, contractile machinery, cytoskeleton scaffold, and energy supply systems. Variations within each compartment are limited by the need of matching fiber type properties between different compartments. Nerve activity is a major control mechanism of the fiber type profile, and multiple signaling pathways are implicated in activity-dependent changes of muscle fibers. The characterization of these pathways is raising increasing interest in clinical medicine, given the potentially beneficial effects of muscle fiber type switching in the prevention and treatment of metabolic diseases.

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“…Whether PDE3A is physically targeted to these putative spatially segregated signaling modules (similar to the association of PDE4 isoforms with AKAP in regulating ryanodine-sensitive channels [ref. 46] or with β-arrestin in downregulation of the β-adrenergic receptor [ref. 47]), and/or regulates their signaling output, is uncertain.…”

Section: Figurementioning

confidence: 99%

Cyclic nucleotide phosphodiesterase 3A–deficient mice as a model of female infertility

Masciarelli¹,

Horner²,

Liu³

et al. 2004

J. Clin. Invest.

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Since cAMP blocks meiotic maturation of mammalian and amphibian oocytes in vitro and cyclic nucleotide phosphodiesterase 3A (PDE3A) is primarily responsible for oocyte cAMP hydrolysis, we generated PDE3A-deficient mice by homologous recombination. The Pde3a -/-females were viable and ovulated a normal number of oocytes but were completely infertile, because ovulated oocytes were arrested at the germinal vesicle stage and, therefore, could not be fertilized. Pde3a -/-oocytes lacked cAMP-specific PDE activity, contained increased cAMP levels, and failed to undergo spontaneous maturation in vitro (up to 48 hours). Meiotic maturation in Pde3a -/-oocytes was restored by inhibiting protein kinase A (PKA) with adenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS) or by injection of protein kinase inhibitor peptide (PKI) or mRNA coding for phosphatase CDC25, which confirms that increased cAMP-PKA signaling is responsible for the meiotic blockade. Pde3a -/-oocytes that underwent germinal vesicle breakdown showed activation of MPF and MAPK, completed the first meiotic division extruding a polar body, and became competent for fertilization by spermatozoa. We believe that these findings provide the first genetic evidence indicating that resumption of meiosis in vivo and in vitro requires PDE3A activity. Pde3a -/-mice represent an in vivo model where meiotic maturation and ovulation are dissociated, which underscores inhibition of oocyte maturation as a potential strategy for contraception.

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Targeting of Protein Kinase A by Muscle A Kinase-anchoring Protein (mAKAP) Regulates Phosphorylation and Function of the Skeletal Muscle Ryanodine Receptor

Cited by 60 publications

References 56 publications

The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling

The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling

Fiber Types in Mammalian Skeletal Muscles

Cyclic nucleotide phosphodiesterase 3A–deficient mice as a model of female infertility

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