Cholesterol efflux to apoA-I in ABCA1-expressing cells is regulated by Ca2+-dependent calcineurin signaling

ATP-binding cassette transporter A1 (ABCA1) is required for the lipidation of apolipoprotein A-I (apoA-I), although molecular mechanisms supporting this process remain poorly defined. In this study, we focused on the role of cytosolic Ca2+ and its signaling and found that cytosolic Ca2+ was required for cholesterol efflux to apoA-I. Removing extracellular Ca2+ or chelating cytosolic Ca2+ were equally inhibitory for apoA-I lipidation. We provide evidence that apoA-I induced Ca2+ influx from the medium. We further demonstrate that calcineurin activity, the downstream target of Ca2+ influx, was essential; inhibition of calcineurin activity by cyclosporine A or FK506 completely abolished apoA-I lipidation. Furthermore, calcineurin inhibition abolished apoA-I binding and diminished JAK2 phosphorylation, an established signaling event for cholesterol efflux to apoA-I. Finally, we demonstrate that neither Ca2+ manipulation nor calcineurin inhibition influenced ABCA1's capacity to release microparticles or to remodel the plasma membrane. We conclude that this Ca2+-dependent calcineurin/JAK2 pathway is specifically responsible for apoA-I lipidation without directly modifying ABCA1 activity. ATP-binding cassette transporter A1 (ABCA1) is required for the lipidation of apolipoprotein A-I (apoA-I), although molecular mechanisms supporting this process remain poorly defined. In this study, we focused on the role of cytosolic Ca2+ and its signaling and found that cytosolic Ca2+ was required for cholesterol efflux to apoA-I. Removing extracellular Ca2+ or chelating cytosolic Ca2+ were equally inhibitory for apoA-I lipidation. We provide evidence that apoA-I induced Ca2+ influx from the medium. We further demonstrate that calcineurin activity, the downstream target of Ca2+ influx, was essential; inhibition of calcineurin activity by cyclosporine A or FK506 completely abolished apoA-I lipidation. Furthermore, calcineurin inhibition abolished apoA-I binding and diminished JAK2 phosphorylation, an established signaling event for cholesterol efflux to apoA-I. Finally, we demonstrate that neither Ca2+ manipulation nor calcineurin inhibition influenced ABCA1's capacity to release microparticles or to remodel the plasma membrane. We conclude that this Ca2+-dependent calcineurin/JAK2 pathway is specifically responsible for apoA-I lipidation without directly modifying ABCA1 activity. ATP-binding cassette transporter A1 (ABCA1) belongs to a large family of evolutionarily conserved transmembrane proteins that transport a wide variety of substrates across the plasma membrane, including ions, drugs, peptides, and lipids. In particular, ABCA1 is a member of the ABC-A subfamily, of which many members transport lipids in multicellular organisms (1Higgins C.F. ABC transporters: physiology, structure and mechanism–an overview.Res. Microbiol. 2001; 152: 205-210Crossref PubMed Scopus (464) Google Scholar). ABCA1 is required to transfer cellular cholesterol to apolipoprotein A-I (apoA-I), leading to the production of HDL. The molecular details of how ABCA1 and apoA-I interact to induce lipidation are largely unknown. In vitro, either lipid-free or lipid-poor apoA-I can induce rapid efflux of both cholesterol and phospholipid from all cell types that express ABCA1. Also, plasma membrane expression of ABCA1 is positively correlated with lipid-free apoA-I association with cells. ABCA1 dysfunctional mutations, which occur in Tangier disease, abolish cholesterol efflux and the cell association of lipid-free apoA-I, clinically resulting in low HDL levels in the circulation (2Nofer J.R. Remaley A.T. Tangier disease: still more questions than answers.Cell. Mol. Life Sci. 2005; 62: 2150-2160Crossref PubMed Scopus (67) Google Scholar). Recent studies have implicated many signaling proteins in ABCA1 function and apoA-I lipidation. For example, no less than 10 kinase pathways have been proposed to modulate posttranslational ABCA1 activity (3Haidar B. Denis M. Krimbou L. Marcil M. Genest Jr, J. cAMP induces ABCA1 phosphorylation activity and promotes cholesterol efflux from fibroblasts.J. Lipid Res. 2002; 43: 2087-2094Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 4Kiss R.S. Maric J. Marcel Y.L. Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux.J. Lipid Res. 2005; 46: 1877-1887Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 5Nofer J.R. Feuerborn R. Levkau B. Sokoll A. Seedorf U. Assmann G. Involvement of Cdc42 signaling in apoA-I-induced cholesterol efflux.J. Biol. Chem. 2003; 278: 53055-53062Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 6Roosbeek S. Peelman F. Verhee A. Labeur C. Caster H. Lensink M.F. Cirulli C. Grooten J. Cochet C. Vandekerckhove J. et al.Phosphorylation by protein kinase CK2 modulates the activity of the ATP binding cassette A1 transporter.J. Biol. Chem. 2004; 279: 37779-37788Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 7Tang C. Vaughan A.M. Oram J.F. Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol.J. Biol. Chem. 2004; 279: 7622-7628Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 8Wang Y. Oram J.F. Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a protein kinase C delta pathway.J. Lipid Res. 2007; 48: 1062-1068Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 9Yamauchi Y. Hayashi M. Abe-Dohmae S. Yokoyama S. Apolipoprotein A-I activates protein kinase C alpha signaling to phosphorylate and stabilize ATP binding cassette transporter A1 for the high density lipoprotein assembly.J. Biol. Chem. 2003; 278: 47890-47897Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 10Martinez L.O. Agerholm-Larsen B. Wang N. Chen W. Tall A.R. Phosphorylation of a pest sequence in ABCA1 promotes calpain degradation and is reversed by ApoA-I.J. Biol. Chem. 2003; 278: 37368-37374Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar). The key signaling molecules in these kinase pathways include protein kinase A (PKA), protein kinase C (PKC), Cdc42, protein kinase 2 (CK2), and Janus Kinase 2 (JAK2). Among these pathways, apoA-I has frequently been implicated as the candidate to initiate signaling processes required for cholesterol efflux. Although several possible mechanisms have been suggested, a clear consensus on which pathway acts as the critical regulator of apoA-I-dependent cholesterol efflux is still lacking. Takahashi and Smith (11Takahashi Y. Smith J.D. Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.Proc. Natl. Acad. Sci. USA. 1999; 96: 11358-11363Crossref PubMed Scopus (204) Google Scholar) reported that extracellular Ca2+ was required for cellular association with apoA-I and apoA-I-dependent cholesterol efflux. It was proposed that Ca2+ was acting as a structural requirement for apoA-I to bind to cell surface receptors, not entirely dissimilar to LDL binding to the LDL receptor (12Basu S.K. Goldstein J.L. Brown M.S. Characterization of the low density lipoprotein receptor in membranes prepared from human fibroblasts.J. Biol. Chem. 1978; 253: 3852-3856Abstract Full Text PDF PubMed Google Scholar). Curiously, Ca2+ is the most ubiquitous and pluripotent signaling molecule and a well-known second messenger that can initiate a diverse array of intracellular signaling events across different spatial and temporal domains. In resting cells, the cytosolic Ca2+ concentration is maintained low levels to the extracellular to cytosolic Ca2+ levels through Ca2+ influx, in with Ca2+ release from intracellular The in cytosolic Ca2+ Ca2+ binding to as binding of a that its binding for a wide array of downstream target proteins S. The of function and Full Text Full Text PDF PubMed Scopus Google Scholar). target proteins of are or these include protein kinase and and In of an that in F. Y. A. M. B. G. an ATP binding cassette transporter required for of cells, a expression in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google we to Ca2+ influx, an intracellular role in apoA-I lipidation through signaling We found in both and cytosolic Ca2+ was required for cholesterol efflux to apoA-I. We provide evidence that apoA-I induced Ca2+ influx cells. We further demonstrate that calcineurin the downstream target of Ca2+ influx and was for cholesterol efflux to apoA-I. Furthermore, inhibition of calcineurin with JAK2 phosphorylation, an established signaling event for cholesterol efflux to apoA-I, and abolished apoA-I Finally, we that neither Ca2+ nor calcineurin inhibition ABCA1 cellular cholesterol or its to remodel the plasma membrane. The Ca2+-dependent pathway is specifically responsible for apoA-I lipidation without directly modifying ABCA1 activity. and and were from were the from Oram and Vaughan of a with or without an ABCA1 The cell was from the was from and from was from which all the of including no The were from several from and was from The and of were from a variety of and The of cellular signaling pathways were from the cyclosporine A FK506 and The and were from The and the were from was from and was from apoA-I was from and were maintained in with in a ABCA1 expression was induced in with which either or for and cells, were as in with cells, was for in with cells. apoA-I was to the to the apoA-I was with and with the was from on a The concentration of was the protein was with for 2 to cell were with different for the of the were from the surface and in of was to of surface proteins that required for apoA-I cell In cells, the were the 2 with the of cells. Finally, of cell association was by The of association was to and were with on for 2 and binding was by and were with with for 2 to to 2 the was with ABCA1 expression was induced with either or as expression of ABCA1 the was with to as the efflux medium. A variety of were in the for 2 or to on cholesterol efflux. apoA-I-dependent apoA-I was in the efflux medium. the of the efflux or was and to cell The was with and were The were in and the of the was Cholesterol efflux was as the the from the efflux and the found in the cell and efflux medium. In cholesterol efflux was as a to the and apoA-I were and in to were with with in for 10 by with in for were with and in for The was a concentration of in a of for with and with for was a concentration of for by a in The cellular of was and a on a with a from ABCA1 and were were to in The were in a and in of for In of apoA-I was in the medium. with was to for were with to activity and surface were with and the cell was a to the cellular influx of the of association with cells, the were in to activity. association was from the cell to for Finally, the protein of was the and all were as a of with of in were and to with for 2 of was directly were for was with a to the was to the The was were with are as The of was by were a that ABCA1 expression on the plasma membrane of F. Y. A. M. B. G. an ATP binding cassette transporter required for of cells, a expression in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Also, Smith et (11Takahashi Y. Smith J.D. Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.Proc. Natl. Acad. Sci. USA. 1999; 96: 11358-11363Crossref PubMed Scopus (204) Google Scholar) reported that extracellular Ca2+ is required for apoA-I lipidation. we were in intracellular Ca2+ signaling in cholesterol efflux to apoA-I. Ca2+ was by Ca2+ to the or cholesterol efflux. and is more for molecules a in cholesterol although was more was was The concentration of that the of is for Also, the inhibition can as as a of Ca2+ is to the We the extracellular Ca2+ and cholesterol efflux to apoA-I. We found that the Ca2+ concentration required for efflux was It is that this is with the extracellular concentration of that a low concentration of extracellular is for cholesterol efflux to apoA-I. A was was the the of cholesterol efflux was high of as all Ca2+ these the of extracellular efflux to apoA-I, as by Smith et (11Takahashi Y. Smith J.D. Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.Proc. Natl. Acad. Sci. USA. 1999; 96: 11358-11363Crossref PubMed Scopus (204) Google Scholar). Although removing extracellular Ca2+ the cell surface or endocytosis (11Takahashi Y. Smith J.D. Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.Proc. Natl. Acad. Sci. USA. 1999; 96: 11358-11363Crossref PubMed Scopus (204) Google Ca2+ influx, a key event for many intracellular signaling intracellular Ca2+ is specifically were with of for is a membrane of a Ca2+ that not bind Ca2+ in its cells, the is by which and to a to specifically intracellular Ca2+ without extracellular Ca2+ We found that abolished cholesterol efflux in a cholesterol efflux was completely the concentration of these Also, by the extracellular Ca2+ concentration Ca2+ we the cholesterol efflux from not for the that intracellular Ca2+ is required for cholesterol efflux to apoA-I. It that removing extracellular Ca2+ most intracellular Ca2+ cholesterol efflux. we found that Ca2+ in cholesterol efflux to apoA-I. Cholesterol efflux from these the to and Ca2+ or to The requirement for extracellular Ca2+ was in the to was in not that intracellular is a required for cholesterol efflux to apoA-I, of cell the that cholesterol efflux to apoA-I Ca2+ influx across the plasma membrane and induces a in cytosolic a by Ca2+ release from intracellular Ca2+ The is a Ca2+ that the in an the receptor and the Ca2+ release the release of Ca2+ from the we as a of the and of the with this the with Ca2+ is through the and the of to the of We found that cholesterol efflux to apoA-I was not by to 10 by J. L. W. Ca2+ signaling in human J. PubMed Google Scholar, A.M. S. and of the of cells: of release and J. PubMed Scopus Google Scholar, A.M. S. ATP from J. PubMed Scopus Google Scholar, L. G. U. A. Ca2+ release by a of in J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) and which and not cholesterol efflux to apoA-I inhibitory C. modulate Ca2+ and Ca2+ in J. 2003; PubMed Scopus Google Scholar, G. release in 2002; PubMed Scopus Google Scholar) of were with no not we conclude that Ca2+ not to the intracellular of Ca2+ that in cholesterol efflux to apoA-I. The of Ca2+ most from the extracellular medium. We apoA-I Ca2+ influx from the extracellular medium. We to in intracellular Ca2+ the cell not in intracellular Ca2+ We this as a that the of Ca2+ influx by apoA-I low that not to we to a to the influx of Ca2+ the from the extracellular medium. In these were to either in the or in the of apoA-I. The of was to that Ca2+ efflux not to the of for the of and cytosolic in PubMed Scopus Google Scholar). Also, was to Ca2+ on the cell surface to of Ca2+ influx to the the influx was by in the We found that influx was in the of apoA-I, apoA-I not influx in that apoA-I induced Ca2+ influx in cells. Ca2+ influx from the extracellular critical for cholesterol efflux to apoA-I. we an of plasma membrane Ca2+ M. G. R. G. with through of Ca2+ PubMed Scopus Google to further Ca2+ was to cholesterol efflux to apoA-I by these demonstrate that apoA-I Ca2+ influx in cells. influx intracellular signaling events required for cholesterol efflux to apoA-I. We the target of intracellular Ca2+ in the process of cholesterol efflux. Ca2+ is as a second messenger to a variety of signaling pathways The and of Mol. Biol. PubMed Scopus Google Scholar). For example, is the target of Ca2+ signaling in The and of Mol. Biol. PubMed Scopus Google Scholar). We is in cholesterol efflux were with cholesterol efflux to apoA-I. is a and the binding of with its downstream substrates H. M. M. of and PubMed Scopus Google Scholar). a inhibition of cholesterol efflux to apoA-I low and and were to which from the of of by Ca2+ is to modulate the function of downstream including and calcineurin The and of Mol. Biol. PubMed Scopus Google Scholar). Although is a the of is to a wide of in cells. is for the and the of these by to J. of in low and high Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Among these calcineurin has the to A. of transport by Biol. Chem. Full Text PDF PubMed Google Scholar) and most to Ca2+ or that Ca2+ influx by apoA-I is of low not by we calcineurin as a candidate in cholesterol efflux to studies reported that cholesterol efflux W. M. G. Smith J.D. A ABCA1 the plasma membrane and efflux to apolipoprotein Biol. 2004; PubMed Scopus Google Scholar, A. C. S. L. Apolipoprotein A-I not are by of ATP-binding cassette transporter A1 and receptor Mol. PubMed Scopus Google Scholar). as an in calcineurin by a with the protein of calcineurin J. J.D. J. is a target of A and Full Text PDF PubMed Scopus Google Scholar). was in the with apoA-I, cholesterol efflux to apoA-I was with inhibition 10 further the of on we calcineurin FK506 to protein that with calcineurin a different from that of H. of calcineurin and its with Res. 2003; PubMed Scopus Google Scholar). that FK506 as a Cholesterol efflux to apoA-I was and was completely abolished of both and FK506 were equally efflux to apoA-I in by calcineurin that are and we conclude that the Ca2+-dependent signaling pathway is for cholesterol efflux to apoA-I. The signaling pathway is to of to initiate The and of Mol. Biol. PubMed Scopus Google Scholar). all the reported were 2 regulation is not to a We to the of ABCA1 We found that ABCA1 protein expression levels and cellular Ca2+ manipulation or calcineurin inhibition is largely with an by Smith et (11Takahashi Y. Smith J.D. Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.Proc. Natl. Acad. Sci. USA. 1999; 96: 11358-11363Crossref PubMed Scopus (204) Google Scholar, W. M. G. Smith J.D. A ABCA1 the plasma membrane and efflux to apolipoprotein Biol. 2004; PubMed Scopus Google Scholar) that inhibition of cholesterol efflux to apoA-I by either or is not to ABCA1 we not ABCA1 expression as by studies (11Takahashi Y. Smith J.D. Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.Proc. Natl. Acad. Sci. USA. 1999; 96: 11358-11363Crossref PubMed Scopus (204) Google Scholar, W. M. G. Smith J.D. A ABCA1 the plasma membrane and efflux to apolipoprotein Biol. 2004; PubMed Scopus Google which to the of or cell The lipidation of apoA-I is to plasma membrane and apoA-I, which a apoA-I association with cells. We apoA-I cell association was was by of apoA-I its in cholesterol efflux as apoA-I not ABCA1 expression induced high levels of apoA-I cell not bind apoA-I completely binding to further the of We found that cell association to to in Ca2+ The of to cell The apoA-I binding is in not extracellular Ca2+ diminished apoA-I cell association not to in binding on the cell intracellular Ca2+ by have intracellular processes required for apoA-I with this we found that both calcineurin abolished apoA-I cell association we found that apoA-I cell association the is positively correlated with the of cholesterol efflux to apoA-I with the apoA-I association and cholesterol efflux ABCA1 A.M. C. Oram J.F. ABCA1 an apoA-I binding activity, and Janus kinase 2 Lipid Res. Full Text Full Text PDF PubMed Scopus (59) Google Scholar). that the Ca2+-dependent signaling pathway is directly responsible for apoA-I with cells. Finally, inhibition of calcineurin signaling with and not ABCA1 expression or not Furthermore, of the or cell as by the Also, with by Takahashi et (11Takahashi Y. Smith J.D. Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.Proc. Natl. Acad. Sci. USA. 1999; 96: 11358-11363Crossref PubMed Scopus (204) Google of Ca2+ from the not apoA-I binding In apoA-I binding was all we cell association in that with and in the of apoA-I of either intracellular or extracellular Ca2+ in apoA-I association inhibition of calcineurin signaling with and FK506 abolished apoA-I association in We conclude that the signaling pathway is for both apoA-I and cholesterol efflux to apoA-I in cells. Oram et reported that JAK2 signaling is for apoA-I and cholesterol efflux to apoA-I C. Vaughan A.M. Oram J.F. Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol.J. Biol. Chem. 2004; 279: 7622-7628Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). JAK2 interact with apoA-I C. Vaughan A.M. Oram J.F. Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol.J. Biol. Chem. 2004; 279: 7622-7628Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, C. Vaughan A.M. Oram J.F. Janus kinase 2 modulates the not interactions of with Lipid Res. Full Text Full Text PDF PubMed Scopus Google and JAK2 phosphorylation positively with apoA-I cell association or cholesterol efflux to apoA-I A.M. C. Oram J.F. ABCA1 an apoA-I binding activity, and Janus kinase 2 Lipid Res. Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Also, JAK2 were in cholesterol efflux to apoA-I C. Vaughan A.M. Oram J.F. Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol.J. Biol. Chem. 2004; 279: 7622-7628Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). we JAK2 phosphorylation in with calcineurin 10 JAK2 phosphorylation Also, the of is to calcineurin Ca2+ influx, of extracellular Ca2+ JAK2 We found JAK2 phosphorylation extracellular Ca2+ was that of JAK2 signaling to apoA-I interactions with and cholesterol efflux. Finally, the Ca2+-dependent signaling pathway to specifically apoA-I binding to not ABCA1 protein expression or we ABCA1 Ca2+-dependent We and reported that ABCA1 expression to cholesterol of apoA-I, to microparticles M. S. Characterization of HDL and microparticles by efflux of cellular lipids to Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, S. L. Denis M. J. cholesterol efflux microparticles in to HDL through processes by membrane Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, Denis M. S. S. Vaughan A.M. ATP-binding cassette transporter A1 expression membrane through its Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Also, ABCA1 the plasma membrane, of apoA-I A.M. Oram J.F. ABCA1 membrane cholesterol of apolipoprotein Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. J. R. et kinase A phosphorylation ATP-binding cassette A1 phospholipid efflux.J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). For the of we these as ABCA1 We with the and production and membrane We found that efflux is completely to the of Ca2+-dependent pathway the abolished cholesterol efflux to apoA-I the pathway is both It is that to efflux which the of was reported to ABCA1 on the plasma membrane, resulting in ABCA1 on the cell surface W. M. G. Smith J.D. A ABCA1 the plasma membrane and efflux to apolipoprotein Biol. 2004; PubMed Scopus Google Scholar). The largely activity in that the not as by the We ABCA1's capacity to remodel the plasma membrane. ABCA1 to from largely to the of the plasma membrane A and to more membrane A.M. Oram J.F. ABCA1 membrane cholesterol of apolipoprotein Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Ca2+-dependent signaling on this ABCA1 still the plasma membrane in cells, from demonstrate that apoA-I specifically the signaling pathway in the calcineurin activity is are ABCA1 still its to remodel the plasma membrane or we conclude that the signaling pathway is a of the cellular that ABCA1 to specifically cholesterol efflux to apoA-I. In this study, we that Ca2+ a critical role in cholesterol efflux to apoA-I. We provide evidence that either of extracellular Ca2+ or intracellular Ca2+ cholesterol efflux to apoA-I. apoA-I Ca2+ influx from the extracellular in cells, which intracellular signaling we found that the signaling pathway was required in cholesterol efflux to apoA-I. and and of completely abolished cholesterol efflux to apoA-I and apoA-I association with cells. We provide evidence that calcineurin through an established signaling event required for cholesterol efflux to apoA-I. the pathway apoA-I lipidation and not the activity of ABCA1. a signaling pathway that ABCA1 specifically to transfer cholesterol on to apoA-I. Although the and ABCA1 activity has not been many studies have the as an ABCA1 We found that either inhibition with or with and cholesterol efflux not that the and the inhibition to plasma membrane we found Ca2+ a more role than is by the apoA-I Ca2+ influx, and that this influx of extracellular or intracellular Ca2+ cholesterol efflux to apoA-I. The of extracellular Ca2+ that a low concentration of extracellular Ca2+ is to cholesterol efflux. with a high concentration of was to completely efflux that the Ca2+ that the pathway is of low is required with or by The and of Mol. Biol. PubMed Scopus Google Scholar). It we were to Ca2+ influx is with the that calcineurin has the for many as of A. of transport by Biol. Chem. Full Text PDF PubMed Google Scholar). It is to that low Ca2+ influx to specifically the pathway without which an as to a can cholesterol efflux to apoA-I The of the Ca2+ and and the no on efflux was in to that which Ca2+ cholesterol efflux to apoA-I by the Ca2+ not further cholesterol efflux not influx through Ca2+ and the of the of Ca2+ cells. of from that low Ca2+ influx induced by apoA-I is to calcineurin influx of Ca2+ through plasma membrane can cholesterol efflux to apoA-I. Ca2+ is to for cholesterol efflux to apoA-I (11Takahashi Y. Smith J.D. Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.Proc. Natl. Acad. Sci. USA. 1999; 96: 11358-11363Crossref PubMed Scopus (204) Google Scholar). We this requirement to Ca2+ influx that activates the calcineurin In of this intracellular Ca2+ by was equally as of extracellular the of in cholesterol efflux to apoA-I has been W. M. G. Smith J.D. A ABCA1 the plasma membrane and efflux to apolipoprotein Biol. 2004; PubMed Scopus Google although the to calcineurin was not defined. both and and calcineurin completely cholesterol to apoA-I calcineurin activity is of the that apoA-I lipidation. was further by the that calcineurin by or Ca2+ JAK2 phosphorylation JAK2 phosphorylation is a for cholesterol efflux to apoA-I. Ca2+ influx and calcineurin of JAK2 It is to that both Ca2+ manipulation and calcineurin inhibition abolish apoA-I cell association apoA-I binding further that Ca2+ and calcineurin function the It that binding of to ABCA1 is not to apoA-I and have to to cholesterol efflux. most this calcineurin pathway is for cholesterol efflux to apoA-I. this pathway has no on ABCA1 cholesterol efflux and plasma membrane a by most its function by the phosphorylation of cellular this ABCA1. function of ABCA1 is to calcineurin activity, is not that ABCA1 is a target of with this JAK2 not directly phosphorylate ABCA1 or to membrane C. Vaughan A.M. Oram J.F. Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol.J. Biol. Chem. 2004; 279: 7622-7628Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). is in with ABCA1 can directly by and phosphorylation of ABCA1 by phospholipid efflux to apoA-I is for ABCA1 function We that calcineurin the phosphorylation of downstream target than to apoA-I lipidation. that apoA-I lipidation on the plasma membrane is not a event apoA-I with membrane In to a of by by and is required to in apoA-I. on this apoA-I cellular to release of apoA-I, diminished apoA-I and of apoA-I lipidation. In we for the that apoA-I induces Ca2+ influx from the extracellular medium. in intracellular Ca2+ activates the pathway to apoA-I cell resulting in cholesterol efflux to apoA-I. with apolipoprotein A-I protein kinase cyclosporine A Ca2+ release receptor

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