α-Kinase Anchoring Protein αKAP Interacts with SERCA2A to Spatially Position Ca2+/Calmodulin-dependent Protein Kinase II and Modulate Phospholamban Phosphorylation

The sarco-endoplasmic reticulum calcium ATPase 2a (SERCA2a) is critical for sequestering cytosolic calcium into the sarco-endoplasmic reticulum (SR) and regulating cardiac muscle relaxation. Protein-protein interactions indicated that it exists in complex with Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its anchoring protein αKAP. Confocal imaging of isolated cardiomyocytes revealed the colocalization of CAMKII and αKAP with SERCA2a at the SR. Deletion analysis indicated that SERCA2a and CaMKII bind to different regions in the association domain of αKAP but not with each other. Although deletion of the putative N-terminal hydrophobic amino acid stretch in αKAP prevented its membrane targeting, it did not influence binding to SERCA2a or CaMKII. Both CaMKIIδC and the novel CaMKIIβ4 isoforms were found to exist in complex with αKAP and SERCA2a at the SR and were able to phosphorylate Thr-17 on phospholamban (PLN), an accessory subunit and known regulator of SERCA2a activity. Interestingly, the presence of αKAP was also found to significantly modulate the Ca2+/calmodulin-dependent phosphorylation of Thr-17 on PLN. These data demonstrate that αKAP exhibits a novel interaction with SERCA2a and may serve to spatially position CaMKII isoforms at the SR and to uniquely modulate the phosphorylation of PLN. The sarco-endoplasmic reticulum calcium ATPase 2a (SERCA2a) is critical for sequestering cytosolic calcium into the sarco-endoplasmic reticulum (SR) and regulating cardiac muscle relaxation. Protein-protein interactions indicated that it exists in complex with Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its anchoring protein αKAP. Confocal imaging of isolated cardiomyocytes revealed the colocalization of CAMKII and αKAP with SERCA2a at the SR. Deletion analysis indicated that SERCA2a and CaMKII bind to different regions in the association domain of αKAP but not with each other. Although deletion of the putative N-terminal hydrophobic amino acid stretch in αKAP prevented its membrane targeting, it did not influence binding to SERCA2a or CaMKII. Both CaMKIIδC and the novel CaMKIIβ4 isoforms were found to exist in complex with αKAP and SERCA2a at the SR and were able to phosphorylate Thr-17 on phospholamban (PLN), an accessory subunit and known regulator of SERCA2a activity. Interestingly, the presence of αKAP was also found to significantly modulate the Ca2+/calmodulin-dependent phosphorylation of Thr-17 on PLN. These data demonstrate that αKAP exhibits a novel interaction with SERCA2a and may serve to spatially position CaMKII isoforms at the SR and to uniquely modulate the phosphorylation of PLN. The phosphorylation/dephosphorylation cycle is critical for controlling a diverse series of signaling processes in cell biology (1Alto N. Carlisle Michel J.J. Dodge K.L. Langeberg L.K. Scott J.D. Diabetes. 2002; 51: S385-S388Crossref PubMed Google Scholar, 2Hudmon A. Schulman H. Annu. Rev. Biochem. 2002; 71: 473-510Crossref PubMed Scopus (525) Google Scholar). Specificity of the phosphorylation/dephosphorylation event is in part achieved by selective employment of a protein kinase/phosphatase cascade and subcellular targeting (1Alto N. Carlisle Michel J.J. Dodge K.L. Langeberg L.K. Scott J.D. Diabetes. 2002; 51: S385-S388Crossref PubMed Google Scholar, 2Hudmon A. Schulman H. Annu. Rev. Biochem. 2002; 71: 473-510Crossref PubMed Scopus (525) Google Scholar). Both spatial and temporal specificity of signaling events is achieved by the compartmentalization of the signaling complexes through adaptor or anchoring proteins (1Alto N. Carlisle Michel J.J. Dodge K.L. Langeberg L.K. Scott J.D. Diabetes. 2002; 51: S385-S388Crossref PubMed Google Scholar, 2Hudmon A. Schulman H. Annu. Rev. Biochem. 2002; 71: 473-510Crossref PubMed Scopus (525) Google Scholar). Recent studies have highlighted novel aspects of integrating spatially and temporally the cAMP signaling cascades via a diverse family of protein kinase A anchoring proteins (AKAPs) 2The abbreviations used are: AKAPprotein kinase A anchoring proteinαKAPα kinase anchoring proteinCaMcalmodulinCaMKIIcalcium-calmodulin-dependent protein kinase IIMSmass spectrometryMALDI-TOFmatrix-assisted laser desorption ionization time-of-flightPLNphospholambanSERCA2asarco-endoplasmic reticulum calcium ATPase 2aGFPgreen fluorescent proteinTBSTris-buffered salineCHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acidMOPS4- morpholinepropanesulfonic acidGSTglutathione S-transferaseTMtransmembrane. (3McConnachie G. Langeberg L.K. Scott J.D. Trends Mol. Med. 2006; 12: 317-323Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). The AKAPs are responsible for positioning the signaling complex via protein-protein interactions for effective and time-sensitive compartmentalization of the cAMP signal (4Smith F.D. Langeberg L.K. Scott J.D. Trends Biochem. Sci. 2006; 31: 316-323Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). protein kinase A anchoring protein α kinase anchoring protein calmodulin calcium-calmodulin-dependent protein kinase II mass spectrometry matrix-assisted laser desorption ionization time-of-flight phospholamban sarco-endoplasmic reticulum calcium ATPase 2a green fluorescent protein Tris-buffered saline 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid 4- morpholinepropanesulfonic acid glutathione S-transferase transmembrane. Although the intracellular targeting of protein kinase A to the effectors is being unraveled, little is known about the targeting of CaMKII activity, which is ubiquitously expressed and serves important roles in calcium signaling to guide synaptic transmission (2Hudmon A. Schulman H. Annu. Rev. Biochem. 2002; 71: 473-510Crossref PubMed Scopus (525) Google Scholar, 5Pitt G.S. Cardiovasc. Res. 2007; 73: 641-647Crossref PubMed Scopus (75) Google Scholar, 6Wayman G.A. Lee Y.S. Tokumitsu H. Silva A. Soderling T.R. Neuron. 2008; 59: 914-931Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar), gene transcription (7Zhang T. Kohlhaas M. Backs J. Mishra S. Phillips W. Dybkova N. Chang S. Ling H. Bers D.M. Maier L.S. Olson E.N. Brown J.H. J. Biol. Chem. 2007; 282: 35078-35087Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar), cell growth (8Kahl C.R. Means A.R. Endocr. Rev. 2003; 24: 719-736Crossref PubMed Scopus (399) Google Scholar), and excitation-contraction coupling (9Yamaguchi N. Meissner G. Circ. Res. 2007; 100: 293-295Crossref PubMed Scopus (12) Google Scholar, 10Stange M. Xu L. Balshaw D. Yamaguchi N. Meissner G. J. Biol. Chem. 2003; 278: 51693-51702Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 11MacLennan D.H. Campbell K.P. Takisawa H. Tuana B.S. Adv. Cyclic Nucleotide Protein Phosphorylation Res. 1984; 17: 393-401PubMed Google Scholar). Although four different isoforms of CaMKII (α, β, δ, and γ) are expressed in a tissue-specific manner, cardiac tissue is shown to have predominance of CaMKIIδC (cytosolic) and CaMKIIδB (nuclear) isoforms, which serve roles in excitation-contraction coupling and cell growth, respectively (7Zhang T. Kohlhaas M. Backs J. Mishra S. Phillips W. Dybkova N. Chang S. Ling H. Bers D.M. Maier L.S. Olson E.N. Brown J.H. J. Biol. Chem. 2007; 282: 35078-35087Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 12Srinivasan M. Edman C.F. Schulman H. J. Cell Biol. 1994; 126: 839-852Crossref PubMed Scopus (237) Google Scholar). Studies have also revealed a significant level of a muscle-specific CaMKII β isoform (CaMKIIβ4) in skeletal and cardiac muscle (11MacLennan D.H. Campbell K.P. Takisawa H. Tuana B.S. Adv. Cyclic Nucleotide Protein Phosphorylation Res. 1984; 17: 393-401PubMed Google Scholar, 13Singh P. Salih M. Leddy J.J. Tuana B.S. J. Biol. Chem. 2004; 279: 35176-35182Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 14Singh P. Leddy J.J. Chatzis G.J. Salih M. Tuana B.S. Mol. Cell. Biochem. 2005; 270: 215-221Crossref PubMed Scopus (9) Google Scholar, 15Bayer K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar). In the gene that kinase in an αKAP in cardiac and skeletal muscle P. Leddy J.J. Chatzis G.J. Salih M. Tuana B.S. Mol. Cell. Biochem. 2005; 270: 215-221Crossref PubMed Scopus (9) Google Scholar, 15Bayer K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar, K.U. J. Harbers K. Mol. Cell. Biol. PubMed Google Scholar). The αKAP a amino acid stretch at the which a putative by the association domain of The association domain in the CaMKII gene family is a important for K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar, K.U. J. Harbers K. Mol. Cell. Biol. PubMed Google Scholar, A. T.R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). αKAP is to to the SR membrane in skeletal muscle via the N-terminal hydrophobic and to the muscle-specific CaMKIIβ4 through with the association domain and calcium K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar). also that αKAP with the novel CaMKIIβ4 are in cardiac SR a for in muscle P. Salih M. Leddy J.J. Tuana B.S. J. Biol. Chem. 2004; 279: 35176-35182Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 14Singh P. Leddy J.J. Chatzis G.J. Salih M. Tuana B.S. Mol. Cell. Biochem. 2005; 270: 215-221Crossref PubMed Scopus (9) Google Scholar, 15Bayer K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar). studies a significant level of a muscle-specific CaMKII β isoform (CaMKIIβ4) in cardiac and skeletal muscle P. Leddy J.J. Chatzis G.J. Salih M. Tuana B.S. Mol. Cell. Biochem. 2005; 270: 215-221Crossref PubMed Scopus (9) Google Scholar, 15Bayer K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar, K.U. J. Harbers K. Mol. Cell. Biol. PubMed Google Scholar). In the gene that kinase in the an αKAP in cardiac and skeletal muscle P. Leddy J.J. Chatzis G.J. Salih M. Tuana B.S. Mol. Cell. Biochem. 2005; 270: 215-221Crossref PubMed Scopus (9) Google Scholar, 15Bayer K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar, K.U. J. Harbers K. Mol. Cell. Biol. PubMed Google Scholar). The αKAP a amino acid stretch at the which a putative by the association domain of The association domain in the CaMKII gene family is a important for K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar, K.U. J. Harbers K. Mol. Cell. Biol. PubMed Google Scholar, A. T.R. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). αKAP is to to the SR membrane in skeletal muscle via the N-terminal hydrophobic and to the muscle-specific CaMKIIβ4 through with the association domain and SR K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar). also that αKAP with the novel CaMKIIβ4 are in cardiac SR a for in muscle P. Salih M. Leddy J.J. Tuana B.S. J. Biol. 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Res. 2005; PubMed Scopus Google Scholar). a in which αKAP serve to modulate phosphorylation and the spatial and temporal on calcium through binding to the calcium ATPase on the and of CaMKII on the other. The of CaMKIIβ4 and αKAP P. Leddy J.J. Chatzis G.J. Salih M. Tuana B.S. Mol. Cell. Biochem. 2005; 270: 215-221Crossref PubMed Scopus (9) Google Scholar). These were in into or and were by In was a the was and were for and was a and The were into or and by an and and were with II of and were at and in with was with to the of cardiomyocytes was the G. P. P. M. D. D. G. G. W. Mol. Cell. Biochem. PubMed Scopus Google Scholar). were with into with and into a cell at was for and the were and in with was and isolated were on of the of were and was to for proteins were in a and at the the was to and were by and at for were by and by in saline was by and was The proteins were isolated on by the for and four with the were with and The was at for and was to and at for at and the SR The was with and for at and for at and the was SR. and proteins were with SR in of for at were four in was and proteins were on of SR was to a in the presence of and with four of with in the but B.S. D.H. PubMed Scopus Google Scholar). Protein were on and membrane and with different or with or to protein that were by analysis at the at the of Protein were also by at the at with different were with for and four with These were with for four and with for four and in The were a to a were in a with and and by was to the in a were and in The was at at for The was and protein was by a and were four with and of cell was with of The was at for and were and with of for each The proteins were on and with different Deletion of αKAP were with in which a was at the of the αKAP The were into or and to Phosphorylation of SERCA2a was by and with or were with and proteins were in calmodulin or and for at the was with of proteins were on and and were on Phosphorylation of was in the presence or of In was with or The of The of proteins was in the phosphorylation that was with for at and with of were on and with or or data have shown that αKAP is a of the SR membrane in skeletal and cardiac muscle P. Salih M. Leddy J.J. Tuana B.S. J. Biol. Chem. 2004; 279: 35176-35182Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 14Singh P. Leddy J.J. Chatzis G.J. Salih M. Tuana B.S. Mol. Cell. Biochem. 2005; 270: 215-221Crossref PubMed Scopus (9) Google Scholar, 15Bayer K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar). In to of were with a SR cardiac The proteins were revealed with of the proteins with to mass revealed that αKAP of and The presence of was not in the with or in also the presence of The a and a and and on and In to the were and and by revealed that αKAP exists in complex with a diverse of proteins A A and and SERCA2a are in the The were and the were in with an which a in the and not in the and in The was and with to the protein of the complex in cardiac A A in a The CaMKII of the SR isolated on calmodulin B.S. D.H. PubMed Scopus Google Scholar). that and CaMKII exist in a proteins on was with SR and proteins with in and B.S. D.H. PubMed Scopus Google Scholar). to a of of different mass and analysis with or revealed that the was the the was the was and the was αKAP of the proteins with a and which have shown to the and respectively P. Salih M. Leddy J.J. Tuana B.S. J. Biol. Chem. 2004; 279: 35176-35182Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 14Singh P. Leddy J.J. Chatzis G.J. Salih M. Tuana B.S. Mol. Cell. Biochem. 2005; 270: 215-221Crossref PubMed Scopus (9) Google Scholar, B.S. D.H. PubMed Scopus Google Scholar). The a the of the calcium ATPase on the SERCA2a and αKAP calmodulin binding P. Leddy J.J. Chatzis G.J. Salih M. Tuana B.S. Mol. Cell. Biochem. 2005; 270: 215-221Crossref PubMed Scopus (9) Google Scholar, K.U. J. Harbers K. Mol. Cell. Biol. PubMed Google Scholar, D.H. Cell. Full Text PDF PubMed Scopus Google Scholar), on the to an association with CaMKII or the B.S. D.H. PubMed Scopus Google Scholar, N. N. Xu L. Meissner G. J. 2007; PubMed Scopus Google Scholar). The binding of but in of mass on the and did not with or of the complex in cardiac in a the interaction of αKAP with SERCA2a and CaMKIIβ4 by of in In a series of of SERCA2a to was with αKAP in and was on cell with analysis with revealed that was in the of cell and not in the of cell The in the with and the level of of SERCA2a protein in and cell and the in the with which the presence of in cell The of not protein of the of the The the were also with which the of SERCA2a protein and the data with the In of was in the with and not in The in the the of in and cell with In the the of αKAP in the cell a in The presence of protein for SERCA2a have A. G. J. G. J. A. J. G. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. K. D. J. Circ. 2006; PubMed Scopus Google Scholar). the interactions αKAP and CaMKII by studies of with and Cell and were for the of The were with and with the presence of CaMKIIβ4 in the of cell and not in cell The were also with which the interaction αKAP and CaMKIIβ4 The and in with and which an αKAP in and in the of but not in and of αKAP with SERCA2a and CaMKIIβ4 by of expressed proteins in in of Confocal of with and that αKAP and SERCA2a on intracellular with a which is a of the reticulum membrane αKAP also on intracellular The SERCA2a to with αKAP was also in of with and a of Both and were in the the was also to through the The subcellular of and CaMKIIβ4 was also in cardiomyocytes with imaging The cardiomyocytes with a and with and that proteins are in a on that subcellular in Although in a a significant of the regions with for αKAP and SERCA2a were also with and the presence of the proteins on the cell and in the A of the of SERCA2a and CaMKIIβ4 in but are regions of for the interactions αKAP and SERCA2a or a series of deletion of αKAP in A and which amino or its different deletion were with or were on cell with and the proteins were by The SERCA2a or CaMKII and a association of the proteins with αKAP. The of αKAP that is for the interaction with SERCA2a in amino binding with SERCA2a is with in αKAP. The in the level of SERCA2a in the different cell The interaction of αKAP with CaMKIIβ4 is by N-terminal of αKAP The with amino interaction with but amino the interaction the and the with amino did not with CaMKIIβ4 The in of CaMKIIβ4 in different deletion cell is the CaMKII isoform in cardiac to αKAP bind and or in was with and the analysis of the protein with that αKAP with CaMKIIβ4 and CaMKIIδC The did not in were also on the to the level of expressed proteins in cell for CaMKIIβ4 CaMKIIδC and The association of and αKAP are and a of with CaMKII αKAP with SERCA2a through a part of its association CaMKII isoforms also with were with and with or isoforms or on cell were with and to and on with revealed that αKAP SERCA2a CaMKIIδC CaMKIIβ4 or with cell were to The in the the of αKAP CaMKIIδC and in different cell The in the of SERCA2a in different cell αKAP is to of an N-terminal by a signal and the association domain of K.U. J. Harbers K. Mol. Cell. Biol. PubMed Google Scholar). the roles of the putative domain to αKAP to intracellular and in the interaction with A deletion of αKAP that the N-terminal amino that are to the domain of αKAP with and were into with were on the cell with and by with revealed that the significant on its SERCA2a binding with the of αKAP to bind SERCA2a also the of and and and in cell In a series of to targeting, αKAP was to and with and were by with the the the deletion a the in the that were with is the that CaMKIIβ4 is a novel cardiac isoform of CAMKII that is to the SR and SERCA2a through αKAP. to the of CaMKIIβ4 to phosphorylate which is a known regulator of SERCA2a and muscle A. L. Cardiovasc. Res. 2005; PubMed Scopus Google Scholar, D.H. Rev. Mol. Cell Biol. 2003; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. Chem. 2007; 282: Full Text Full Text PDF PubMed Scopus Google Scholar, L.S. T. L. J. Brown J.H. Bers D.M. Circ. Res. 2003; PubMed Scopus Google Scholar). The of CaMKII or to phosphorylate SERCA2a or its subunit phospholamban was in that were with and isoforms or were with and the proteins were to The were in and by which the presence of of and phosphorylation were in the presence of and but not phosphorylation was in in the of and is that phosphorylation of the which was in was to CaMKIIδC or CaMKIIβ4 The CaMKIIδC is known to phosphorylate Thr-17 on phospholamban and SERCA2a A. L. Cardiovasc. Res. 2005; PubMed Scopus Google Scholar). CaMKIIβ4 also serve to phosphorylate phospholamban by with CaMKIIδC or CaMKIIβ4 proteins and for the phosphorylation of analysis of proteins with revealed that CaMKIIδC and CaMKIIβ4 are able to phosphorylation of in a and with the CaMKIIδC and CaMKIIβ4 Phosphorylation of by CaMKIIδC in the presence of may to the level of of A was also and a of it was in the and The was and with a to in the The the with to the level of CaMKIIδC and for or with are also shown and In to αKAP modulate and CaMKIIβ4 were expressed proteins and to phosphorylation in the presence and of αKAP. analysis of with was used to on phospholamban and αKAP in a phosphorylation with or The the of CaMKIIδC by with and αKAP by with The with and the the with for CaMKIIδC to phosphorylation of with that in the presence of phosphorylation was by the presence of αKAP The the of CaMKIIβ4 by with and αKAP by with The with and the the with CaMKIIβ4 to phosphorylation of with The phosphorylation of was by the presence of αKAP Although the it also with a of mass in the of the by that in the presence of αKAP was a in the phosphorylation of to CaMKII The data that αKAP exist in a complex with CaMKII isoforms, and at the cardiac SR. αKAP SERCA2a CaMKIIδC and CaMKIIβ4 isoforms, which are in cardiac αKAP modulate phosphorylation at which is known to SERCA2a and SR A. L. Cardiovasc. Res. 2005; PubMed Scopus Google Scholar, D.H. Rev. Mol. Cell Biol. 2003; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. Chem. 2007; 282: Full Text Full Text PDF PubMed Scopus Google Scholar, L.S. T. L. J. Brown J.H. Bers D.M. Circ. Res. 2003; PubMed Scopus Google Scholar). SERCA2a to regions in the association domain of αKAP that are that with CaMKII. Although the of the putative domain of αKAP it the SR K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar, A. A. A. K.U. P. Biochem. J. 2003; PubMed Google Scholar), it did not its interaction with SERCA2a or the association domain of αKAP the binding is the CaMKII isoforms did not interactions with a for the αKAP interactions in positioning at the SR The CaMKIIδC and CaMKIIβ4 were effective in on and the presence of αKAP was found to phosphorylation The phosphorylation of on Thr-17 to CaMKIIδC or at by protein kinase A with an in SERCA2a activity, calcium and the of cardiac muscle D.H. Rev. Mol. Cell Biol. 2003; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. Chem. 2007; 282: Full Text Full Text PDF PubMed Scopus Google Scholar, L.S. T. L. J. Brown J.H. Bers D.M. Circ. Res. 2003; PubMed Scopus Google Scholar). The of CaMKIIβ4 isoform to exist in a complex with αKAP and SERCA2a and phosphorylate Thr-17 on that kinase serve a in cardiac muscle In studies that that CaMKIIδC in the and to H. T. L. Means H. K.L. J. Bers D. Brown J. J. PubMed Scopus Google Scholar). In of data on the and targeting of CaMKIIβ4 to cardiac that CaMKII isoform for CaMKIIδC and to cardiac biology and the to in the CaMKIIδC H. T. L. Means H. K.L. J. Bers D. Brown J. J. PubMed Scopus Google Scholar). CaMKIIβ4 bind and at the SR and in the of to calcium P. Salih M. Leddy J.J. Tuana B.S. J. Biol. Chem. 2004; 279: 35176-35182Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 14Singh P. Leddy J.J. Chatzis G.J. Salih M. Tuana B.S. Mol. Cell. Biochem. 2005; 270: 215-221Crossref PubMed Scopus (9) Google Scholar). the data on CaMKIIβ4 and its at the SR membrane an important and for CaMKII isoform in cardiac is that the CaMKIIδC isoform in and its in excitation-contraction cardiac growth, and L.S. T. L. J. Brown J.H. Bers D.M. Circ. Res. 2003; PubMed Scopus Google Scholar). Although data that αKAP CaMKIIδC and CaMKIIβ4 isoforms to the SR to modulate it is that of bind to was SERCA2a a of protein the association of αKAP with SERCA2a may critical for positioning CaMKII for the of calcium via phosphorylation of PLN. position αKAP a membrane protein that with SERCA2a on the and CaMKII on the other. In αKAP a and an adaptor to the spatial positioning of proteins to the of SERCA2a through phosphorylation by CaMKII at the SR. a of a complex at the SR which calcium and to the calcium in a and temporal the cytosolic to calcium the it bind and CaMKII to phosphorylate and the on SERCA2a and calcium into the SR and muscle D.H. Rev. Mol. Cell Biol. 2003; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. Chem. 2007; 282: Full Text Full Text PDF PubMed Scopus Google Scholar, L.S. T. L. J. Brown J.H. Bers D.M. Circ. Res. 2003; PubMed Scopus Google Scholar). αKAP modulate the level of phosphorylation on Thr-17 and SR Although αKAP shown to with and K.U. Harbers K. Schulman H. EMBO J. 1998; 17: 5598-5605Crossref PubMed Scopus (110) Google Scholar), it modulate CaMKIIδC and CaMKIIβ4 and the level of phosphorylation on Thr-17 at the SR membrane to is that is critical for the spatial and temporal of cAMP and a of AKAPs have that for targeting cAMP signaling to subcellular (3McConnachie G. Langeberg L.K. Scott J.D. Trends Mol. Med. 2006; 12: 317-323Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, F.D. Langeberg L.K. Scott J.D. Trends Biochem. Sci. 2006; 31: 316-323Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). and skeletal muscle tissue have to of which are critical in the anchoring of protein kinase A to the the N. N. J. Cell Sci. PubMed Google Scholar), calcium T. Sci. 2003; 100: PubMed Scopus Google Scholar), or C.R. K. T. J. D. W. M. K. EMBO 2007; PubMed Scopus Google and and J. Res. 2006; PubMed Scopus Google Scholar, S. J.H. M. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). that αKAP with membrane proteins of the and in and imaging that αKAP exhibits subcellular the αKAP may a part of different intracellular membrane complexes that CaMKII isoforms to effectors to influence a of events and the of CaMKII (2Hudmon A. Schulman H. Annu. Rev. Biochem. 2002; 71: 473-510Crossref PubMed Scopus (525) Google Scholar). the diverse of the AKAPs in cAMP signaling cascades N. Langeberg L.K. Scott J.D. Cell Biol. 2005; PubMed Scopus Google Scholar), it is that αKAP may an for the spatial and temporal of signaling at subcellular In the calcium is also a for CaMKII H. T. L. Means H. K.L. J. Bers D. Brown J. J. PubMed Scopus Google Scholar), and the of αKAP in its targeting and is also J. and M. for and

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