Regulation of the rat brain Na+
-driven Cl-/HCO3- exchanger involves protein kinase A and a multiprotein signaling complex

ABSTRACT Spatial and temporal resolution of intracellular signaling can be achieved by compartmentalizing transduction units. Myopodin is a dual-compartment, actin-bundling protein that shuttles between the nucleus and the Z-disc of myocytes in a differentiation- and stress-dependent fashion. Importin α binding and nuclear import of myopodin are regulated by serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3. Here we show that in the heart myopodin forms a Z-disc signaling complex with α-actinin, calcineurin, Ca2+/calmodulin-dependent kinase II (CaMKII), muscle-specific A-kinase anchoring protein, and myomegalin. Phosphorylation of myopodin by protein kinase A (PKA) or CaMKII mediates 14-3-3 binding and nuclear import in myoblasts. Dephosphorylation of myopodin by calcineurin abrogates 14-3-3β binding. Activation of PKA or inhibition of calcineurin in adult cardiac myocytes releases myopodin from the Z-disc and induces its nuclear import. The identification of myopodin as a direct target of PKA, CaMKII, and calcineurin defines a novel intracellular signaling pathway whereby changes in Z-disc dynamics may translate into compartmentalized signal transduction in the heart.

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Erratum: Lee et al., In Vivo and In Vitro Ethanol Exposure in Prenatal Rat Brain: GABABReceptor Modulation on Dopamine D1Receptor and Protein Kinase A. Synapse 62:534-543, DOI 20522

Synapse ◽

10.1002/syn.20790 ◽

2010 ◽

Vol 64 (7) ◽

pp. 578-578

Keyword(s):

Protein Kinase ◽

Protein Kinase A ◽

Rat Brain ◽

Ethanol Exposure ◽

Kinase A

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mAKAP and the ryanodine receptor are part of a multi-component signaling complex on the cardiomyocyte nuclear envelope

Journal of Cell Science ◽

10.1242/jcs.114.17.3167 ◽

2001 ◽

Vol 114 (17) ◽

pp. 3167-3176

Author(s):

Michael S. Kapiloff ◽

Nicole Jackson ◽

Nathan Airhart

Keyword(s):

Protein Kinase ◽

Nuclear Envelope ◽

Protein Kinase A ◽

Ryanodine Receptor ◽

Calcium Ion ◽

Calcium Release ◽

Ryanodine Receptors ◽

Scaffolding Protein ◽

Signaling Complex ◽

Kinase A

The physical association of regulatory enzymes and ion channels at relevant intracellular sites contributes to the diversity and specificity of second messenger-mediated signal transduction in cells. mAKAP is a scaffolding protein that targets the cAMP-dependent protein kinase A and phosphodiesterase type 4D3 to the nuclear envelope of differentiated cardiac myocytes. Here we present data that the mAKAP signaling complex also includes nuclear envelope-resident ryanodine receptors and protein phosphatase 2A. The ryanodine receptor is the major cardiac ion channel responsible for calcium-induced calcium release from intracellular calcium ion stores. As demonstrated by a combination of immunohistochemistry and tissue fractionation, mAKAP is targeted specifically to the nuclear envelope, whereas the ryanodine receptor is present at both the sarcoplasmic reticulum and nuclear envelope intracellular membrane compartments. At the nuclear envelope, a subset of cardiac ryanodine receptor is bound to mAKAP and via the association with mAKAP may be regulated by protein kinase A-mediated phosphorylation. By binding protein kinase A and ryanodine receptor, mAKAP may serve as the scaffold for a cAMP- and calcium ion-sensitive signaling complex.

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Protein kinase A phosphorylation enhances sodium channel currents in Xenopus oocytes

AJP Cell Physiology ◽

10.1152/ajpcell.1992.263.3.c660 ◽

1992 ◽

Vol 263 (3) ◽

pp. C660-C666 ◽

Cited By ~ 73

Author(s):

R. D. Smith ◽

A. L. Goldin

Keyword(s):

Protein Kinase ◽

Sodium Channel ◽

Protein Kinase A ◽

Rat Brain ◽

Xenopus Oocytes ◽

Kinase Inhibitor ◽

Sodium Current ◽

Specific Inhibitor ◽

Channel Currents ◽

Kinase A

The voltage-sensitive rat brain sodium channel is known to be phosphorylated by adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase A (PKA), but the functional significance of that phosphorylation is unknown. We have shown that rat brain sodium channel currents expressed in Xenopus oocytes were enhanced by induction of PKA activity. Stimulation of the beta 2-adrenergic receptor or treatment with dibutyryl cAMP resulted in increased sodium current amplitudes without affecting the voltage dependence of channel activation or inactivation. These increases were completely blocked by preinjection of protein kinase inhibitor, a specific inhibitor of PKA. Injection of phosphatase into the oocytes resulted in a significant decrease in sodium current amplitude, indicating that phosphorylation is important for basal levels of sodium channel activity in oocytes. The enhancement was specific for the rat brain IIA sodium channel, because currents expressed from the rat muscle microI sodium channel were not enhanced by the same procedures. These data demonstrate a modulatory role of PKA phosphorylation on brain sodium channel function and suggest a means by which the electrical excitability of cells may be regulated.

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