{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:21:44Z","timestamp":1791336104788,"version":"4.3.1"},"reference-count":57,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2014,12,24]],"date-time":"2014-12-24T00:00:00Z","timestamp":1419379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["[Grant HL085487] (B.K.M.)"],"award-info":[{"award-number":["[Grant HL085487] (B.K.M.)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Beta-adrenergic receptors (\u03b2-ARs) stimulation enhances contractility through protein kinase-A (PKA) substrate phosphorylation. This PKA signaling is conferred in part by PKA binding to A-kinase anchoring proteins (AKAPs). AKAPs coordinate multi-protein signaling networks that are targeted to specific intracellular locations, resulting in the localization of enzyme activity and transmitting intracellular actions of neurotransmitters and hormones to its target substrates. In particular, mAKAP (muscle-selective AKAP) has been shown to be present on the nuclear envelope of cardiomyocytes with various proteins including: PKA-regulatory subunit (RII\u03b1), phosphodiesterase-4D3, protein phosphatase-2A, and ryanodine receptor (RyR2). Therefore, through the coordination of spatial-temporal signaling of proteins and enzymes, mAKAP controls cyclic-adenosine monophosphate (cAMP) levels very tightly and functions as a regulator of PKA-mediated substrate phosphorylation leading to changes in calcium availability and myofilament calcium sensitivity. The goal of this review is to elucidate the critical compartmentalization role of mAKAP in mediating PKA signaling and regulating cardiomyocyte hypertrophy by acting as a scaffolding protein. Based on our literature search and studying the structure\u2013function relationship between AKAP scaffolding protein and its binding partners, we propose possible explanations for the mechanism by which mAKAP promotes cardiac hypertrophy.<\/jats:p>","DOI":"10.3390\/ijms16010218","type":"journal-article","created":{"date-parts":[[2014,12,24]],"date-time":"2014-12-24T11:51:41Z","timestamp":1419421901000},"page":"218-229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Compartmentalization Role of A-Kinase Anchoring Proteins (AKAPs) in Mediating Protein Kinase A (PKA) Signaling and Cardiomyocyte Hypertrophy"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4619-2012","authenticated-orcid":false,"given":"Abeer","family":"Rababa'h","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, Jordan University of Science and Technology,  Irbid 22110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonal","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, University of Houston,  Texas Medical Center, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh","family":"Suryavanshi","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, University of Houston,  Texas Medical Center, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salah","family":"Altarabsheh","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Queen Alia Heart Institute, Amman 11953, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salil","family":"Deo","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"McConnell","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, University of Houston,  Texas Medical Center, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,12,24]]},"reference":[{"key":"ref_1","first-page":"D678","article-title":"Specificity in the cAMP\/PKA signaling pathway. Differential expression, regulation, and subcellular localization of subunits of PKA","volume":"5","author":"Skalhegg","year":"2000","journal-title":"Front. Biosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1242\/jcs.114.17.3167","article-title":"mAKAP and the ryanodine receptor are part of a multi-component signaling complex on the cardiomyocyte nuclear envelope","volume":"114","author":"Kapiloff","year":"2001","journal-title":"J. Cell Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/0163-7258(91)90075-W","article-title":"Cyclic nucleotide-dependent protein kinases","volume":"50","author":"Scott","year":"1991","journal-title":"Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1096\/fasebj.8.15.8001734","article-title":"Multiple pathway signal transduction by the cAMP-dependent protein kinase","volume":"8","author":"Walsh","year":"1994","journal-title":"FASEB J."},{"key":"ref_5","first-page":"283","article-title":"Activation of cAMP-dependent protein kinase without a corresponding increase in phosphorylase activity","volume":"18","author":"Keely","year":"1977","journal-title":"Res. Commun. Chem. Pathol. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/262615a0","article-title":"Phosphorylation of troponin I and the inotropic effect of adrenaline in the perfused rabbit heart","volume":"262","author":"Solaro","year":"1976","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1093\/oxfordjournals.jbchem.a123735","article-title":"Phosphorylation of ryanodine receptors in rat myocytes during beta-adrenergic stimulation","volume":"111","author":"Yoshida","year":"1992","journal-title":"J. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1161\/01.CIR.103.6.889","article-title":"Interactions between phospholamban and beta-adrenergic drive may lead to cardiomyopathy and early mortality","volume":"103","author":"Dash","year":"2001","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/415198a","article-title":"Cardiac excitation-contraction coupling","volume":"415","author":"Bers","year":"2002","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1002\/iub.168","article-title":"A-kinase anchoring proteins: from protein complexes to physiology and disease","volume":"61","author":"Carnegie","year":"2009","journal-title":"IUBMB Life"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"24145","DOI":"10.1074\/jbc.M802278200","article-title":"Phosphorylation of the cAMP-dependent protein kinase (PKA) regulatory subunit modulates PKA-AKAP interaction, substrate phosphorylation, and calcium signaling in cardiac cells","volume":"283","author":"Manni","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1161\/res.89.5.373","article-title":"When is cAMP not cAMP? Effects of compartmentalization","volume":"89","author":"Bers","year":"2001","journal-title":"Circ. Res."},{"key":"ref_13","first-page":"467","article-title":"A kinase anchor proteins and the intracellular targeting of signals carried by cyclic AMP","volume":"1224","author":"Rubin","year":"1994","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/S0962-8924(99)01558-5","article-title":"AKAPs: From structure to function","volume":"9","author":"Colledge","year":"1999","journal-title":"Trends Cell. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/nature03966","article-title":"The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways","volume":"437","author":"Soughayer","year":"2005","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9079","DOI":"10.1074\/jbc.M110.160614","article-title":"Small molecule AKAP-protein kinase A (PKA) interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes","volume":"286","author":"Christian","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"33708","DOI":"10.1074\/jbc.M804807200","article-title":"Dual specificity A-kinase anchoring proteins (AKAPs) contain an additional binding region that enhances targeting of protein kinase A type I","volume":"283","author":"Jarnaess","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.molcel.2006.09.006","article-title":"Molecular basis of AKAP specificity for PKA regulatory subunits","volume":"24","author":"Gold","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1161\/CIRCRESAHA.108.174813","article-title":"Protein kinase A type I and type II define distinct intracellular signaling compartments","volume":"103","author":"Zoccarato","year":"2008","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12881","DOI":"10.1074\/jbc.272.20.12881","article-title":"Protein kinase A anchoring","volume":"272","author":"Scott","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1161\/01.RES.0000218273.91741.30","article-title":"Compartmentation of cyclic nucleotide signaling in the heart: The role of A-kinase anchoring proteins","volume":"98","author":"Langeberg","year":"2006","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.molcel.2006.09.015","article-title":"A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase","volume":"24","author":"Kinderman","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"41389","DOI":"10.1074\/jbc.M004212200","article-title":"Selectivity and regulation of A-kinase anchoring proteins in the heart. The role of autophosphorylation of the type II regulatory subunit of cAMP-dependent protein kinase","volume":"275","author":"Zakhary","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1152\/physiol.00041.2008","article-title":"AKAP-scaffolding proteins and regulation of cardiac physiology","volume":"24","author":"Mauban","year":"2009","journal-title":"Physiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1093\/emboj\/17.8.2261","article-title":"A novel lipid-anchored A-kinase Anchoring Protein facilitates cAMP-responsive membrane events","volume":"17","author":"Fraser","year":"1998","journal-title":"EMBO J."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Johnson, K.R., Nicodemus-Johnson, J., Carnegie, G.K., and Danziger, R.S. (2012). Molecular evolution of A-kinase anchoring protein (AKAP)-7: Implications in comparative PKA compartmentalization. BMC Evol. Biol., 12.","DOI":"10.1186\/1471-2148-12-125"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17099","DOI":"10.1073\/pnas.1215219109","article-title":"Cardiomyocytes from AKAP7 knockout mice respond normally to adrenergic stimulation","volume":"109","author":"Jones","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0896-6273(00)80358-X","article-title":"cAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits","volume":"19","author":"Gao","year":"1997","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1083\/jcb.142.2.511","article-title":"A-kinase anchoring protein 100 (AKAP100) is localized in multiple subcellular compartments in the adult rat heart","volume":"142","author":"Yang","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0092-8674(00)80847-8","article-title":"PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): Defective regulation in failing hearts","volume":"101","author":"Marx","year":"2000","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.yexcr.2004.10.009","article-title":"Nesprin-1\u03b1 contributes to the targeting of mAKAP to the cardiac myocyte nuclear envelope","volume":"303","author":"Pare","year":"2005","journal-title":"Exp. Cell Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.1242\/jcs.112.16.2725","article-title":"mAKAP: An A-kinase anchoring protein targeted to the nuclear membrane of differentiated myocytes","volume":"112","author":"Kapiloff","year":"1999","journal-title":"J. Cell Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1161\/CIRCHEARTFAILURE.114.001266","article-title":"The scaffold protein muscle A-kinase anchoring protein beta orchestrates cardiac myocyte hypertrophic signaling required for the development of heart failure","volume":"7","author":"Kritzer","year":"2014","journal-title":"Circ. Heart Fail."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8215","DOI":"10.1128\/MCB.00950-07","article-title":"Protein kinase A, Ca2+\/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes","volume":"27","author":"Faul","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e74784","DOI":"10.1371\/journal.pone.0074784","article-title":"Enhanced cardiac function in gravin mutant mice involves alterations in the beta-adrenergic receptor signaling cascade","volume":"8","author":"Guillory","year":"2013","journal-title":"PLoS One"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1161\/01.RES.88.3.291","article-title":"AKAP-mediated targeting of protein kinase a regulates contractility in cardiac myocytes","volume":"88","author":"Fink","year":"2001","journal-title":"Circ. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1074\/jbc.M806321200","article-title":"Disruption of protein kinase A interaction with A-kinase-anchoring proteins in the heart in vivo: Effects on cardiac contractility, protein kinase A phosphorylation, and troponin I proteolysis","volume":"284","author":"McConnell","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20990","DOI":"10.1073\/pnas.0710527105","article-title":"Mutation of an A-kinase-anchoring protein causes long-QT syndrome","volume":"104","author":"Chen","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3277","DOI":"10.1016\/j.jmb.2013.06.014","article-title":"Protein kinase A and phosphodiesterase-4D3 binding to coding polymorphisms of cardiac muscle anchoring protein (mAKAP)","volume":"425","author":"Craft","year":"2013","journal-title":"J. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.molcel.2005.10.013","article-title":"Spatial restriction of PDK1 activation cascades by anchoring to mAKAP\u03b1","volume":"20","author":"Michel","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9327","DOI":"10.1074\/jbc.270.16.9327","article-title":"Cloning and characterization of A-kinase anchor protein 100 (AKAP100). A protein that targets A-kinase to the sarcoplasmic reticulum","volume":"270","author":"McCartney","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1242\/jcs.02416","article-title":"A-kinase-anchoring proteins","volume":"118","author":"Langeberg","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.yjmcc.2011.05.002","article-title":"AKAPs: The architectural underpinnings of local cAMP signaling","volume":"52","author":"Kritzer","year":"2012","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1093\/emboj\/20.8.1921","article-title":"mAKAP assembles a protein kinase A\/PDE4 phosphodiesterase cAMP signaling module","volume":"20","author":"Dodge","year":"2001","journal-title":"EMBO J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1042\/BJ20040846","article-title":"PKA-phosphorylation of PDE4D3 facilitates recruitment of the mAKAP signalling complex","volume":"381","author":"Dodge","year":"2004","journal-title":"Biochem. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1161\/01.RES.0000233386.02708.72","article-title":"Sarcoplasmic reticulum and nuclear envelope are one highly interconnected Ca2+ store throughout cardiac myocyte","volume":"99","author":"Wu","year":"2006","journal-title":"Circ. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1161\/CIRCRESAHA.114.300569","article-title":"Role of RyR2 phosphorylation in heart failure and arrhythmias: Protein kinase A-mediated hyperphosphorylation of the ryanodine receptor at serine 2808 does not alter cardiac contractility or cause heart failure and arrhythmias","volume":"114","author":"Houser","year":"2014","journal-title":"Circ. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1161\/CIRCRESAHA.114.300568","article-title":"Role of RyR2 phosphorylation in heart failure and arrhythmias: Controversies around ryanodine receptor phosphorylation in cardiac disease","volume":"114","author":"Dobrev","year":"2014","journal-title":"Circ. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1080\/15216540701358593","article-title":"The mAKAP signalosome and cardiac myocyte hypertrophy","volume":"59","author":"Bauman","year":"2007","journal-title":"IUBMB Life"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cell.2005.07.030","article-title":"Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias","volume":"123","author":"Lehnart","year":"2005","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1161\/CIRCRESAHA.112.273839","article-title":"Local control of nuclear calcium signaling in cardiac myocytes by perinuclear microdomains of sarcolemmal insulin-like growth factor 1 receptors","volume":"112","author":"Ibarra","year":"2013","journal-title":"Circ. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0092-8674(00)81573-1","article-title":"A calcineurin-dependent transcriptional pathway for cardiac hypertrophy","volume":"93","author":"Molkentin","year":"1998","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.1242\/jcs.02675","article-title":"The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling","volume":"118","author":"Pare","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1083\/jcb.126.6.1565","article-title":"Mitogen-activated protein kinases mediate changes in gene expression, but not cytoskeletal organization associated with cardiac muscle cell hypertrophy","volume":"126","author":"Thorburn","year":"1994","journal-title":"J. Cell Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1093\/emboj\/16.8.1888","article-title":"MAP kinase- and Rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells","volume":"16","author":"Thorburn","year":"1997","journal-title":"EMBO J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.yjmcc.2009.11.006","article-title":"Nesprin-1 mutations in human and murine cardiomyopathy","volume":"48","author":"Puckelwartz","year":"2010","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.cell.2013.02.047","article-title":"Phospholipase Cepsilon hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy","volume":"153","author":"Zhang","year":"2013","journal-title":"Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/1\/218\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:11:37Z","timestamp":1760217097000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/1\/218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,24]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,1]]}},"alternative-id":["ijms16010218"],"URL":"https:\/\/doi.org\/10.3390\/ijms16010218","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,24]]}}}