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• W2017821806 abstract "The nuclear factor of activated T cells (NFAT) was discovered as an inducible transcription factor activated by antigen stimulation of the T cell receptor in lymphocytes. Stimulation of NFAT-mediated transcription is now reported in both lymphoid and non-lymphoid cells following activation of a neurotransmitter receptor. Carbachol induces robust luciferase responses in Jurkat and pheochromocytoma PC12 cells expressing an NFAT-luciferase reporter construct and a Gq-coupled m3 muscarinic receptor. Cyclosporin blocks this response in PC12 cells, as in Jurkat cells. In PC12 cells expressing a Gi-coupled m2 muscarinic receptor, carbachol induces NFAT-mediated luciferase activity that is strictly dependent upon co-expression of a chimeric Gαq/αi subunit, which confers Gq-effector coupling on Gi-linked receptors. These findings suggest that neurotransmitters, autacoids, or hormones acting on Gq-protein-coupled receptors may serve as physiological stimulators of NFAT in lymphoid and non-lymphoid cells. The nuclear factor of activated T cells (NFAT) was discovered as an inducible transcription factor activated by antigen stimulation of the T cell receptor in lymphocytes. Stimulation of NFAT-mediated transcription is now reported in both lymphoid and non-lymphoid cells following activation of a neurotransmitter receptor. Carbachol induces robust luciferase responses in Jurkat and pheochromocytoma PC12 cells expressing an NFAT-luciferase reporter construct and a Gq-coupled m3 muscarinic receptor. Cyclosporin blocks this response in PC12 cells, as in Jurkat cells. In PC12 cells expressing a Gi-coupled m2 muscarinic receptor, carbachol induces NFAT-mediated luciferase activity that is strictly dependent upon co-expression of a chimeric Gαq/αi subunit, which confers Gq-effector coupling on Gi-linked receptors. These findings suggest that neurotransmitters, autacoids, or hormones acting on Gq-protein-coupled receptors may serve as physiological stimulators of NFAT in lymphoid and non-lymphoid cells. The nuclear factor of activated T cells (NFAT), 1The abbreviations used are: NFATnuclear factor of activated T cellsTCRT cell receptorPLCphospholipase CPKCprotein kinase CIL-2interleukin 2FBSfetal bovine serumNFAT-luciferasefirefly luciferase reporter plasmidpRSV-Tagplasmid encoding the SV40 large T antigenCsAcyclosporin APMAphorbol 12-myristate 13-acetate. a transcription factor activated by antigen stimulation of the T cell receptor (TCR), is known mainly for its role in the co-ordinate induction of interleukin and cytokine genes during immune cell activation(1.Shaw J.P. Utz P.J. Durand D.B. Toole J.J. Emmel E.A. Crabtree G.R. Science. 1988; 241: 202-215Crossref PubMed Scopus (10) Google Scholar). Stimulation of the TCR and subsequent protein-tyrosine phosphorylation initiates several downstream events, including the activation of γ isoforms of phospholipase C (PLCγ). PLCγ, like other PLC isoforms, catalyzes the breakdown of phosphoinositides. The resultant co-activation of Ca2+ and protein kinase C (PKC) signaling pathways is required for induction of NFAT-mediated transcription(2.Weiss A. Littman D.R. Cell. 1994; 76: 263-274Abstract Full Text PDF PubMed Scopus (1957) Google Scholar, 3.Rao A. Immunol. Today. 1994; 15: 274-281Abstract Full Text PDF PubMed Scopus (490) Google Scholar, 4.Szamel M. Resch K. Eur. J. Biochem. 1995; 228: 1-15Crossref PubMed Scopus (87) Google Scholar). nuclear factor of activated T cells T cell receptor phospholipase C protein kinase C interleukin 2 fetal bovine serum firefly luciferase reporter plasmid plasmid encoding the SV40 large T antigen cyclosporin A phorbol 12-myristate 13-acetate. Stimulation of receptors coupled to the Gq subfamily of heterotrimeric G-proteins activates β isoforms of PLC (PLCβ), and thus the possibility exists that such receptors may participate in induction of NFAT-dependent gene expression. Previous experiments have shown that stimulation of an ectopically expressed muscarinic receptor in T cells induces phosphoinositide hydrolysis(5.Goldsmith M.A. Desai D.M. Schultz T. Weiss A. J. Biol. Chem. 1989; 264: 17190-17197Abstract Full Text PDF PubMed Google Scholar), interleukin 2 (IL-2) production(6.Desai D.M. Newton M.E. Kadlecek T. Weiss A. Nature. 1990; 348: 66-69Crossref PubMed Scopus (99) Google Scholar), and lymphoid NFAT activity(7.Wu J. Katzav S. Weiss A. Mol. Cell. Biol. 1995; 15: 4337-4346Crossref PubMed Scopus (167) Google Scholar). Gq-protein-coupled receptors are expressed in many cell types, and NFAT or NFAT-like activities have recently been discovered in a variety of lymphoid and non-lymphoid cells and tissues(1.Shaw J.P. Utz P.J. Durand D.B. Toole J.J. Emmel E.A. Crabtree G.R. Science. 1988; 241: 202-215Crossref PubMed Scopus (10) Google Scholar, 8.Verweij C.L. Guidos C. Crabtree G.R. J. Biol. Chem. 1990; 265: 15788-15795Abstract Full Text PDF PubMed Google Scholar, 9.Yaseen N.R. Maizel A.L. Wang F. Sharma S. J. Biol. Chem. 1993; 268: 14285-14293Abstract Full Text PDF PubMed Google Scholar, 10.Choi M.S.K. Brines R.D. Holman M.J. Klaus G.G.B. Immunity. 1994; 1: 179-187Abstract Full Text PDF PubMed Scopus (127) Google Scholar, 11.Ho A.M. Jain J. Rao A. Hogan P.G. J. Biol. Chem. 1994; 269: 28181-28186Abstract Full Text PDF PubMed Google Scholar, 12.Ventkataraman L. Francis D.A. Wang Z. Liu J. Rothstein T.L. Sen R. Immunity. 1994; 1: 189-196Abstract Full Text PDF PubMed Scopus (106) Google Scholar, 13.Cockerill G.W. Bert A.G. Ryan G.R. Gamble J.R. Vadas M.A. Cockerill P.N. Blood. 1995; 7: 2689-2698Crossref Google Scholar, 14.Hoey T. Sun Y-L. Williamson K. Xu X. Immunity. 1995; 2: 461-472Abstract Full Text PDF PubMed Scopus (354) Google Scholar, 15.Weiss D.L. Hural J. Tara D. Timmerman L.A. Henkel G. Brown M.A. Mol. Cell. Biol. 1996; 16: 228-235Crossref PubMed Scopus (69) Google Scholar). The present study demonstrates that NFAT can act as a downstream effector of Gq-protein-coupled receptors in the non-lymphoid PC12 cell line, as well as in lymphoid cells. A plasmid containing multimers of the NFAT binding site located upstream from the minimal IL-2 promoter and the firefly luciferase reporter gene (NFAT-luciferase) (16.Northrop J.P. Ulman K.S. Crabtree G.R. J. Biol. Chem. 1993; 268: 2917-2923Abstract Full Text PDF PubMed Google Scholar) was a gift from Rick Bram (St. Jude Children's Research Hospital, Memphis, TN). Plasmids coding for human muscarinic receptors m2 and m3 (17.Bonner T.I. Buckley N.J. Young A.C. Brann M.R. Science. 1987; 237: 527-532Crossref PubMed Scopus (1222) Google Scholar) were obtained from Allan Levey (Emory University, Atlanta, GA). Plasmids encoding G-protein α subunits (wild type Gαq, and a chimera, Gαq/αi, in which the last five residues from αi are replaced with corresponding amino acids from Gαq(18.Conklin B.R. Farfel Z. Lustig K.D. Julius D. Bourne H.R. Nature. 1993; 363: 274-276Crossref PubMed Scopus (615) Google Scholar)) were gifts from Bruce Conklin (Gladstone Cardiovascular Center, San Francisco, CA). Jurkat cells and PC12 cells (subcolony originated by Simon Haleguoa, SUNY, Stonybrook, NY) were obtained from Jeremy Boss and Ken Minneman, respectively (Emory University). Cells (0.8 ml) were electroporated in a 0.4-cm gap cuvette using a Bio-Rad Gene Pulser II at 950 microfarads and 300 V (for Jurkat cells) or 360 V (for PC12 cells), at cell densities of 1 × 107 cells/ml (for Jurkat cells) or 3-7 × 106 cells/ml (for PC12 cells). NFAT-luciferase plasmid DNA (10 μg) and pRSV-Tag plasmid DNA (5 μg), as well as 5 μg of each additional plasmid DNA, were included in every transfection, and all transfections were performed in duplicate in RPMI 1640 medium. Transfected cells were aliquoted in multiwell plates in RPMI 1640 with 10-20% FBS (for Jurkat) or Dulbecco's modified Eagle's medium with 10% FBS (for PC12) with penicillin/streptomycin and maintained at 37°C (5% CO2). For luciferase assays, receptor agonists and other drugs were added to Jurkat or PC12 cells between 46 and 50 h after transfection. After an additional 8-12 h, cells were harvested, and luciferase activity was determined as described previously(19.Takeuchi K. Alexander R.W. Nakamura Y. Tsujino T. Murphy T.J. Circ. Res. 1993; 73: 612-621Crossref PubMed Scopus (94) Google Scholar). For phosphoinositide hydrolysis assays, fresh growth medium containing 1 μCi/ml myo-[3H]inositol (Amersham Corp.) was added at 36 h after transfection. After an additional 18 h of incubation, agonists and additional drugs were added to fresh medium containing 5 mM LiCl, and the incubation was continued for 60 min. Cells were lysed and [3H]inositol phosphates were measured as described previously(20.Murphy T.J. Nakamura Y. Takeuchi K. Alexander R.W. Mol. Pharmacol. 1993; 44: 1-7PubMed Google Scholar). RPMI 1640 and bicarbonate-buffered Dulbecco's modified Eagle's medium used for growth media were made from powder obtained from Life Technologies, Inc. The RPMI 1640 (liquid) used for transfections, FBS, and calf serum were purchased from Cellgro Mediatech (Herndon, VA), and horse serum was from Atlanta Biologicals (Norcross, GA). Carbachol, ionomycin, phorbol 12-myristate 13-acetate (PMA), and chemicals for buffers were purchased from Sigma. Firefly luciferin was obtained from Boehringer Mannheim. Cyclosporin A (CsA) was a gift from Sandoz Pharmaceuticals (Basel, Switzerland). Transcriptional responses to Ca2+ and PKC establish the salient features of NFAT-mediated gene expression in lymphoid (Jurkat) and non-lymphoid (PC12) cells. These were transfected with a well characterized NFAT-inducible luciferase reporter plasmid containing a concatemer of the distal IL-2 gene NFAT-responsive element on a minimal IL-2 gene promoter(16.Northrop J.P. Ulman K.S. Crabtree G.R. J. Biol. Chem. 1993; 268: 2917-2923Abstract Full Text PDF PubMed Google Scholar, 21.Bram R.J. Crabtree G.R. Nature. 1994; 371: 355-358Crossref PubMed Scopus (143) Google Scholar), as well as a plasmid encoding the SV40 large T antigen (pRSV-Tag) to ensure plasmid replication. In Jurkat cells (n = 4 experiments) and in PC12 cells (n = 3 experiments), the respective basal luciferase responses in the absence of added drugs (0.04 ± 0.01 and 0.06 ± 0.02 Turner light units; mean ± S.E.) are near the lower limit of detectability. The PKC activator PMA does not significantly stimulate luciferase activity in either cell line. In Jurkat cells, the Ca2+ ionophore ionomycin induces a modest increase in luciferase activity (5.5 ± 1.6-fold over basal). Consistent with previous reports(1.Shaw J.P. Utz P.J. Durand D.B. Toole J.J. Emmel E.A. Crabtree G.R. Science. 1988; 241: 202-215Crossref PubMed Scopus (10) Google Scholar, 7.Wu J. Katzav S. Weiss A. Mol. Cell. Biol. 1995; 15: 4337-4346Crossref PubMed Scopus (167) Google Scholar, 16.Northrop J.P. Ulman K.S. Crabtree G.R. J. Biol. Chem. 1993; 268: 2917-2923Abstract Full Text PDF PubMed Google Scholar, 22.Clipstone N.A. Crabtree G.R. Nature. 1992; 357: 695-697Crossref PubMed Scopus (1477) Google Scholar), ionomycin and PMA together elicit synergistic stimulation of luciferase activity (550 ± 170-fold over basal) (Fig. 1a). Similarly, in PC12 cells, modest luciferase responses elicited by ionomycin alone (5.3 ± 1.4-fold) are potentiated by PMA (13 ± 3-fold in PC12 cells) (Fig. 1b). NFAT-mediated responses induced by ionomycin in PC12 cells exhibit dose-related increases at concentrations up to 1 μM, which attenuate at higher concentrations (Fig. 1c). Virtually identical results have been obtained using ionomycin in Jurkat cells (data not shown)(22.Clipstone N.A. Crabtree G.R. Nature. 1992; 357: 695-697Crossref PubMed Scopus (1477) Google Scholar). These data suggest that PC12 cells, like Jurkat cells, express a functional NFAT capable of mediating transcriptional events in response to Ca2+ and PKC signaling. TCR activation of PLCγ defines the major known pathway for induction of NFAT-mediated transcription in lymphocytes. Recent studies suggest that lymphoid NFAT may also be induced through stimulation of receptors that activate PLCβ through coupling to heterotrimeric Gq-proteins(6.Desai D.M. Newton M.E. Kadlecek T. Weiss A. Nature. 1990; 348: 66-69Crossref PubMed Scopus (99) Google Scholar, 7.Wu J. Katzav S. Weiss A. Mol. Cell. Biol. 1995; 15: 4337-4346Crossref PubMed Scopus (167) Google Scholar). Carbachol (1 mM) elevates luciferase activity (410 ± 44-fold increase; n = 5 experiments) in Jurkat cells expressing a muscarinic m3 receptor but not in cells transfected with empty vector as control (Fig. 2a). Similarly, carbachol elicits a dose-dependent increase in luciferase activity that is 34 ± 7-fold over basal at the highest dose applied (1 mM carbachol) in PC12 cells expressing the m3 receptor but not in control cells transfected with empty vector (n = 5 experiments) (Fig. 2b). Carbachol-induced phosphoinositide hydrolysis and luciferase responses in PC12 cells were compared in side-by-side experiments. Both responses were elicited in cells expressing the m3 receptor but not in those transfected with empty vector instead (Table 1), although luciferase measurements clearly serve as a more sensitive indicator of receptor stimulation than inositol phosphate responses.TABLE 1TABLE 1 A chimeric Gαq/αi subunit that switches the coupling of Gi-linked receptors from inhibition of adenylate cyclase to stimulation of PLC (18.Conklin B.R. Farfel Z. Lustig K.D. Julius D. Bourne H.R. Nature. 1993; 363: 274-276Crossref PubMed Scopus (615) Google Scholar) was used to establish that heterotrimeric G-proteins are involved in muscarinic receptor-induced NFAT responses. PC12 cells were transfected with reporter plasmids, and either an empty vector, a plasmid coding for a wild type Gαq, or a plasmid coding for Gαq/αi was added. A dose-related increase in carbachol-stimulated luciferase activity is elicited in PC12 cells expressing Gαq/αi alone but not in control cells expressing wild type Gαq (Fig. 2c) or transfected with empty vector (data not shown). This response is likely mediated by a muscarinic m4 receptor endogenous to PC12 cells, which is known to couple negatively to adenylate cyclase(23.Pinkas-Kramarski R. Edelman R. Stein R. Neurosci. Lett. 1990; 108: 335-340Crossref PubMed Scopus (23) Google Scholar). In parallel experiments, larger dose-related increases in carbachol-stimulated luciferase activity are elicited in cells expressing a Gi-coupled m2 receptor, and these responses are strictly dependent upon the presence of Gαq/αi (Fig. 2c). Carbachol elicits both phosphoinositide hydrolysis and NFAT-luciferase responses in side-by-side assays in PC12 cells expressing the m2 receptor in the presence, but not the absence, of the chimeric Gαq/αi subunit (Table 1). Since the chimeric G-protein complements a response otherwise refractory in the cells, the simplest interpretation of these data is that Gq-protein coupling is both necessary and sufficient for induction of NFAT-mediated transcription by muscarinic receptors. The immunosuppressant CsA forms a complex with a cyclophilin that inhibits calcineurin, a Ca2+-dependent phosphatase essential for the nuclear translocation of NFAT and subsequent NFAT-dependent transcription(22.Clipstone N.A. Crabtree G.R. Nature. 1992; 357: 695-697Crossref PubMed Scopus (1477) Google Scholar, 24.Flanagan M.W. Corthésy B. Bram R.J. Crabtree G.R. Nature. 1991; 352: 803-807Crossref PubMed Scopus (954) Google Scholar, 25.Liu J. Farmer Jr., J.D. Lane W.S. Schreiber S.L. Cell. 1991; 66: 807-815Abstract Full Text PDF PubMed Scopus (3634) Google Scholar, 26.O'Keefe S.J. Tamura J. Kincaid R.L. Tocci M.J. O'Neill E.A. Nature. 1992; 357: 692-694Crossref PubMed Scopus (788) Google Scholar). As in Jurkat cells (data not shown) (22.Clipstone N.A. Crabtree G.R. Nature. 1992; 357: 695-697Crossref PubMed Scopus (1477) Google Scholar) Ca2+- and PKC-dependent NFAT activation in PC12 cells is inhibited by CsA at concentrations consistent with its effects on immune cells(21.Bram R.J. Crabtree G.R. Nature. 1994; 371: 355-358Crossref PubMed Scopus (143) Google Scholar, 22.Clipstone N.A. Crabtree G.R. Nature. 1992; 357: 695-697Crossref PubMed Scopus (1477) Google Scholar, 24.Flanagan M.W. Corthésy B. Bram R.J. Crabtree G.R. Nature. 1991; 352: 803-807Crossref PubMed Scopus (954) Google Scholar, 26.O'Keefe S.J. Tamura J. Kincaid R.L. Tocci M.J. O'Neill E.A. Nature. 1992; 357: 692-694Crossref PubMed Scopus (788) Google Scholar, 27.Brabletz T. Pietrowski I. Serfling E. Nucleic Acids Res. 1991; 19: 61-67Crossref PubMed Scopus (75) Google Scholar, 28.McCaffrey P.A. Perrino B.A. Soderling T.R. Rao A. J. Biol. Chem. 1993; 268: 3747-3752Abstract Full Text PDF PubMed Google Scholar). CsA also inhibits carbachol-induced luciferase expression in cells expressing the m3 receptor (Fig. 3). Co-dependence of NFAT activation upon elevations of intracellular Ca2+ and PKC activity and its sensitivity to CsA are principal characteristics of NFAT activity (for reviews, see (2.Weiss A. Littman D.R. Cell. 1994; 76: 263-274Abstract Full Text PDF PubMed Scopus (1957) Google Scholar, 3.Rao A. Immunol. Today. 1994; 15: 274-281Abstract Full Text PDF PubMed Scopus (490) Google Scholar, 4.Szamel M. Resch K. Eur. J. Biochem. 1995; 228: 1-15Crossref PubMed Scopus (87) Google Scholar)). Therefore, the finding that m3 receptor-stimulated luciferase responses are blocked by CsA in PC12 cells provides further evidence that Gq-protein-coupled receptors can mediate NFAT induction in non-immune cells. This study establishes that NFAT transcription factors can serve as downstream effectors for Gq-protein-coupled receptors that activate PLC and that such receptors can induce NFAT activity in both lymphoid and non-lymphoid cells. NFAT proteins or NFAT-like DNA binding and/or transcriptional activities and NFAT isoform mRNA have been identified in a variety of tissues (8.Verweij C.L. Guidos C. Crabtree G.R. J. Biol. Chem. 1990; 265: 15788-15795Abstract Full Text PDF PubMed Google Scholar, 14.Hoey T. Sun Y-L. Williamson K. Xu X. Immunity. 1995; 2: 461-472Abstract Full Text PDF PubMed Scopus (354) Google Scholar) and cell types, including lymphoid(1.Shaw J.P. Utz P.J. Durand D.B. Toole J.J. Emmel E.A. Crabtree G.R. Science. 1988; 241: 202-215Crossref PubMed Scopus (10) Google Scholar, 9.Yaseen N.R. Maizel A.L. Wang F. Sharma S. J. Biol. Chem. 1993; 268: 14285-14293Abstract Full Text PDF PubMed Google Scholar, 10.Choi M.S.K. Brines R.D. Holman M.J. Klaus G.G.B. Immunity. 1994; 1: 179-187Abstract Full Text PDF PubMed Scopus (127) Google Scholar, 12.Ventkataraman L. Francis D.A. Wang Z. Liu J. Rothstein T.L. Sen R. Immunity. 1994; 1: 189-196Abstract Full Text PDF PubMed Scopus (106) Google Scholar), endothelial(13.Cockerill G.W. Bert A.G. Ryan G.R. Gamble J.R. Vadas M.A. Cockerill P.N. Blood. 1995; 7: 2689-2698Crossref Google Scholar), neuronal(11.Ho A.M. Jain J. Rao A. Hogan P.G. J. Biol. Chem. 1994; 269: 28181-28186Abstract Full Text PDF PubMed Google Scholar), and mast cells(15.Weiss D.L. Hural J. Tara D. Timmerman L.A. Henkel G. Brown M.A. Mol. Cell. Biol. 1996; 16: 228-235Crossref PubMed Scopus (69) Google Scholar). Receptors coupled to Gq-proteins are represented in numerous cell types and respond to a diverse array of hormones, autacoids, and neurotransmitters. The present studies indicate that these agents are capable of acting as physiological activators of NFAT and that NFAT-mediated transcription represents a heretofore unappreciated mechanism by which these receptor agonists can modulate cellular physiology. Furthermore, immunosuppressant therapy with CsA is limited by its toxicity to neural, hepatic, bone, and renal systems. The present findings raise the possibility that some of these side effects might arise in part through disruption of normal cellular processes that are modulated by virtue of Gq-protein-coupled receptor regulation of NFAT-mediated transcriptional activities. We are grateful to Drs. Jeremy Boss, Melissa Brown, Ray Dingledine, and Ken Minneman for thoughtful comments and to Drs. Rick Bram, Bruce Conklin, and Allan Levey for supplying plasmids." @default.
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• W2017821806 title "Induction of NFAT-mediated Transcription by Gq-coupled Receptors in Lymphoid and Non-lymphoid Cells" @default.
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