Differential Effects of Ca2+ and cAMP on Transcription Mediated by MEF2D and cAMP-response Element-binding Protein in Hippocampal Neurons

Abstract

In neurons, the second messengers Ca2+ and cAMP are mediators of transcriptional responses that are important for the development and function of the nervous system. The pro-survival neuronal transcription factors cAMP-response elementbinding protein (CREB) and myocyte enhancer factor-2 (MEF2) both stimulate gene expression in response to activity-dependent increases in the concentration of intracellular Ca2+ ions. CREB is also activated by increases in intracellular cAMP. Here we have investigated whether the MEF2 family member MEF2D, similar to CREB, is also activated by cAMP in hippocampal neurons. We have shown that, unlike CREB, MEF2D is not activated by agents that increase intracellular cAMP. Moreover, increases in cAMP inhibit Ca2+-activated MEF2D-mediated gene expression. We have also shown that cAMP inhibits Ca2+-induced nuclear export of the MEF2 co-repressor HDAC5 and prevents Ca2+-stimulated nuclear import of the MEF2 co-activator NFAT3/c4. Our results suggest that cAMP interferes with MEF2D-mediated gene expression at multiple levels by antagonizing the derepression of MEF2D by HDAC5 and by inhibiting recruitment of the co-activator NFAT. In neurons, the second messengers Ca2+ and cAMP are mediators of transcriptional responses that are important for the development and function of the nervous system. The pro-survival neuronal transcription factors cAMP-response elementbinding protein (CREB) and myocyte enhancer factor-2 (MEF2) both stimulate gene expression in response to activity-dependent increases in the concentration of intracellular Ca2+ ions. CREB is also activated by increases in intracellular cAMP. Here we have investigated whether the MEF2 family member MEF2D, similar to CREB, is also activated by cAMP in hippocampal neurons. We have shown that, unlike CREB, MEF2D is not activated by agents that increase intracellular cAMP. Moreover, increases in cAMP inhibit Ca2+-activated MEF2D-mediated gene expression. We have also shown that cAMP inhibits Ca2+-induced nuclear export of the MEF2 co-repressor HDAC5 and prevents Ca2+-stimulated nuclear import of the MEF2 co-activator NFAT3/c4. Our results suggest that cAMP interferes with MEF2D-mediated gene expression at multiple levels by antagonizing the derepression of MEF2D by HDAC5 and by inhibiting recruitment of the co-activator NFAT. The transcription factors cAMP-response element-binding protein (CREB) 3The abbreviations used are: CREB, cAMP-response element-binding protein; HDAC, histone deacetylase; MEF2, myocyte enhancer factor-2; GFP, green fluorescent protein; NFAT, nuclear factor of activated T cells; NMDA, N-methyl-d-aspartate; PBS, phosphate-buffered saline; PKA, cAMP-dependent protein kinase; ERK, extracellular signal-regulated kinase; CPT-cAMP, 8-(4-chlorophenylthio)adenosine-3′, 5′-cyclic monophosphate; LTP, long term potentiation; GSK, glycogen synthase kinase; MADS, MCM1 Agamons Deficiens serum-response factor. and myocyte enhancer factor-2 (MEF2) regulate gene expression in neurons that is required for neuronal differentiation, survival, and plasticity. During development of the central nervous system and in the adult brain, gene expression is regulated by various stimuli such as neurotrophins and synaptic activity. Often, the interaction between different intracellular signaling cascades initiated by concurrent exposure to a range of stimuli elicits specific transcriptional responses that determine neuronal fate. Although CREB regulation in neurons has been the subject of many investigations that have demonstrated CREB activation by the second messengers Ca2+ and cAMP and by neurotrophins (reviewed in Ref. 1Lonze B.E. Ginty D.D. Neuron. 2002; 35: 605-623Abstract Full Text Full Text PDF PubMed Scopus (1748) Google Scholar), the regulation of MEF2 transcription factors by similar stimuli is not yet fully understood. MEF2 proteins belong to the MADS box family of transcription factors, which contain a conserved N-terminal domain (present in MCM1, Agamous, Deficiens, and serum response factor) and which were initially identified in muscle where they regulate many muscle-specific genes and influence myogenesis. Subsequent studies revealed high expression of MEF2 factors in the brain, where they have emerged as regulators of activity-dependent neuronal survival and differentiation, and in immune cells, where they are involved in mediating T cell activation (reviewed in Ref. 2McKinsey T.A. Zhang C.L. Olson E.N. Trends Biochem. Sci. 2002; 27: 40-47Abstract Full Text Full Text PDF PubMed Scopus (589) Google Scholar). Four MEF2 family members (MEF2A, MEF2B, MEF2C, and MEF2D), each encoded by a different gene, have been identified in mammalian cells. The pro-survival effects of MEF2 have been demonstrated in response to activity-induced Ca2+ signals and in response to neurotrophins, which regulate MEF2 by distinct mechanisms. Although neuronal activity-dependent survival of adult cortical and cerebellar neurons mediated by MEF2 is regulated by the Ca2+-dependent kinases p38 mitogen-activated protein kinase (MAPK) (3Mao Z. Bonni A. Xia F. Nadal-Vicens M. Greenberg M.E. Science. 1999; 286: 785-790Crossref PubMed Scopus (446) Google Scholar) and Ca2+/calmodulin-dependent kinase II (CaMKII) (4Linseman D.A. Bartley C.M. Le S.S. Laessig T.A. Bouchard R.J. Meintzer M.K. Li M. Heidenreich K.A. J. Biol. Chem. 2003; 278: 41472-41481Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar), the survival-promoting actions of neurotrophins in developing cortical neurons (5Liu L. Cavanaugh J.E. Wang Y. Sakagami H. Mao Z. Xia Z. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 8532-8537Crossref PubMed Scopus (142) Google Scholar) and cerebellar granule neurons (6Shalizi A. Lehtinen M. Gaudilliere B. Donovan N. Han J. Konishi Y. Bonni A. J. Neurosci. 2003; 23: 7326-7336Crossref PubMed Google Scholar) are attributed to the activation of MEF2-dependent gene expression by ERK5. The second messenger cAMP has also been implicated in promoting the survival of many types of neurons (7Hanson Jr., M.G. Shen S. Wiemelt A.P. McMorris F.A. Barres B.A. J. Neurosci. 1998; 18: 7361-7371Crossref PubMed Google Scholar, 8Li M. Wang X. Meintzer M.K. Laessig T. Birnbaum M.J. Heidenreich K.A. Mol. Cell. Biol. 2000; 20: 9356-9363Crossref PubMed Scopus (335) Google Scholar). This survival-promoting effect of cAMP is likely due to its effect on CREB, because CREB-mediated gene expression is induced by cAMP as well as by pro-survival signals such as neurotrophins and Ca2+. In addition to CREB, cAMP may also influence MEF2 activity. Because MEF2, similar to CREB, is clearly activated by synaptic activity-induced Ca2+ transients (3Mao Z. Bonni A. Xia F. Nadal-Vicens M. Greenberg M.E. Science. 1999; 286: 785-790Crossref PubMed Scopus (446) Google Scholar) and by neurotrophic factors (5Liu L. Cavanaugh J.E. Wang Y. Sakagami H. Mao Z. Xia Z. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 8532-8537Crossref PubMed Scopus (142) Google Scholar, 6Shalizi A. Lehtinen M. Gaudilliere B. Donovan N. Han J. Konishi Y. Bonni A. J. Neurosci. 2003; 23: 7326-7336Crossref PubMed Google Scholar), here we have investigated whether MEF2 family members similar to CREB are also activated by increases in intracellular cAMP in hippocampal neurons. We compared the activation of CREB with the MEF2 isoform MEF2D that is expressed highly in the hippocampus (9Ikeshima H. Imai S. Shimoda K. Hata J. Takano T. Neurosci. Lett. 1995; 200: 117-120Crossref PubMed Scopus (40) Google Scholar, 10Lin X. Shah S. Bulleit R.F. Brain Res. Mol. Brain Res. 1996; 42: 307-316Crossref PubMed Scopus (81) Google Scholar). We report that, unlike CREB, MEF2D-mediated gene expression is not induced by increases in intracellular cAMP in hippocampal neurons, although an increase in intracellular Ca2+ stimulates both transcription factors. Not only did cAMP fail to activate MEF2D, it antagonized Ca2+-activation of MEF2D-mediated gene expression. CREB, however, was activated synergistically by concurrent increases in Ca2+ and cAMP. MEF2 transcription factors are regulated by several Ca2+-dependent mechanisms that operate at many levels. In quiescent cells, MEF2 proteins are bound to and repressed by class II histone deacetylases, which include HDAC4, -5, -7, and -9. This repression is relieved during synaptic activity in hippocampal neurons when Ca2+ influx through L-type voltage-gated calcium channels or synaptic NMDA receptors induces nuclear export of HDAC4 and 5 (11Chawla S. Vanhoutte P. Arnold F.J.L. Huang C.L. Bading H. J. Neurochem. 2003; 85: 151-159Crossref PubMed Scopus (253) Google Scholar). MEF2 proteins freed from HDAC repression are subject to further Ca2+-dependent regulation by p38 MAPK, ERK5, and the Ca2+/calmodulin-dependent phosphatase calcineurin (reviewed in Ref. 2McKinsey T.A. Zhang C.L. Olson E.N. Trends Biochem. Sci. 2002; 27: 40-47Abstract Full Text Full Text PDF PubMed Scopus (589) Google Scholar). Calcineurin acts to control MEF2-mediated gene expression in several ways. Calcineurin can act directly and maintain MEF2 in a hypophosphorylated state, which enhances the DNA binding affinity of MEF2 (12Mao Z. Wiedmann M. J. Biol. Chem. 1999; 274: 31102-31107Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar) and also protects it from caspase-mediated cleavage (13Li M. Linseman D.A. Allen M.P. Meintzer M.K. Wang X. Laessig T. Wierman M.E. Heidenreich K.A. J. Neurosci. 2001; 21: 6544-6552Crossref PubMed Google Scholar). Calcineurin can also influence MEF2-mediated gene expression indirectly by regulating the subcellular localization of the nuclear factor of activated T family of transcription factors, which act as MEF2 T.A. J. 2000; PubMed Scopus Google Scholar, F. N. T.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of proteins in the by calcineurin the where they with and F. N. T.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and recruitment of protein T.A. J. 2000; PubMed Scopus Google Scholar) to activate MEF2-mediated gene expression. We have shown here that the of MEF2 activity by cAMP also at many levels and may multiple mechanisms. we that cAMP inhibits the Ca2+-activated nuclear export of the MEF2 co-repressor we that cAMP also Ca2+-induced nuclear import of the MEF2 co-activator NFAT3/c4. and neurons from were as H. Greenberg M.E. Science. PubMed Scopus Google Scholar), that the was with was to the to inhibit of cells. for was a from C.M. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). The expression the DNA binding domain with CREB was as S. C.M. Bading H. PubMed Scopus Google Scholar). for DNA binding and the gene DNA binding have been F. N. T.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). was from The was by F. N. T.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and to of the The was by of H. R.J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). and neurons were in were or for as and were in H. Greenberg M.E. Science. PubMed Scopus Google Scholar), and activity was with the to the of the a activity was to the and were in were on neuronal Ca2+ neurons on for were with by with in for by a further for in the of were in an in a and with of and at were and are shown as in neurons were in in for with in for and by in in for 5 at the with were with the in at with and with both in PBS, were for each at were with and in protein were with in for and in of and were an system with an were as or both nuclear and or nuclear The of in each was neurons in were and the by the in at for The were with for 5 and with in for at The was and were for with by with in for at were with and in were in at on a system of were 5 Ca2+ and cAMP on and MEF2D-mediated the effects of Ca2+ and cAMP on and MEF2D-mediated gene expression by a gene system. neurons were with a a MEF2D protein the DNA binding domain to MEF2D with a gene DNA binding in the F. N. T.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). CREB-mediated gene expression was by a protein with the were with extracellular to activate Ca2+ influx the through L-type calcium activate Ca2+ influx through synaptic NMDA neurons were with in the of the This of that are by NMDA Ca2+ transients Y. Bading H. Neurosci. 2002; PubMed Scopus Google Scholar). We that Ca2+ influx through L-type calcium channels or synaptic NMDA receptors in a and of MEF2D-mediated gene expression when compared with control and CREB-mediated gene expression was induced by Ca2+ influx through both increases in gene expression can attributed to MEF2D and CREB, as the DNA binding domain on its to expression of the gene in response to increases in intracellular Ca2+ We compared the effects of intracellular cAMP on and MEF2D-mediated gene expression. of neurons with the to activate MEF2D-mediated gene expression although in a activation of CREB-mediated transcription were with both and the of MEF2D by MEF2D-mediated gene expression activation of synaptic NMDA receptors with not In and synergistically to CREB-mediated gene expression The of CREB-mediated gene expression by increases in intracellular cAMP and Ca2+ has been on In cells, cAMP and Ca2+ have been shown to act synergistically to transcription of the gene J. Neurochem. PubMed Scopus Google Scholar). similar of second messengers has been on the of the gene in cortical neurons M. A. M. J. Sci. PubMed Scopus Google Scholar). cAMP Ca2+-activated MEF2D-mediated that cAMP has an effect on Ca2+ activation of MEF2D, we used to increase intracellular cAMP levels. of with the MEF2D-mediated gene expression to of the This is similar to the of with which the activity to Because hippocampal neurons receptors D.D. A. R.J. T. Science. 2001; PubMed Scopus Google Scholar) that activate we used the as an of cAMP levels. the MEF2D-mediated increase in gene expression by cAMP levels by of the cAMP activation of that intracellular cAMP Ca2+ activation of MEF2D in hippocampal neurons. Because the used a we investigated the effect of cAMP on transcription of a MEF2 gene in neurons. of the nuclear gene is regulated by MEF2 transcription factors in immune T.A. J. 2000; PubMed Scopus Google Scholar, F. N. T.A. J. Biol. 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We the effects of intracellular cAMP on HDAC5 subcellular neurons were with a a and HDAC5 localization was by in hippocampal neurons that synaptic HDAC5 was nuclear in a of cells, both nuclear and in of cells, and in of cells. with high extracellular induced HDAC5 nuclear export with a localization of HDAC5 and of with in a of HDAC5 the with nuclear localization compared with in neurons and revealed that HDAC5 in the results that cAMP activity-induced nuclear export of nuclear a in the with several of This of HDAC5 localization in the is similar to that in when HDAC5 was with the for and receptors X. Li H. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The of HDAC5 was to gene expression X. Li H. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In hippocampal neurons, when and HDAC5 are they in nuclear which can from P. S. Bading H. S. M. J. Neurochem. PubMed Scopus Google Scholar). The of HDAC5 here may of HDAC5 nuclear by or by whether cAMP inhibits HDAC5 nuclear were with and This also in a nuclear localization of HDAC5 in of cells. We also localization of HDAC5 protein a to HDAC5 and that Ca2+-induced nuclear export of HDAC5 was by cAMP cAMP inhibits both activity and nuclear export of that by which cAMP inhibits MEF2D is by the Ca2+-activated derepression of MEF2D from of cAMP and Ca2+ on HDAC5 HDAC5 localization in hippocampal neurons for was with a HDAC5 from were or with or or and for and for as and The are of results in is the of MEF2D is required for Ca2+ activation of MEF2D-mediated gene expression. neurons were with and as in the to were with or or and activity was activity is to control II MEF2 proteins at the N-terminal a conserved MADS box and a conserved MEF2 protein the domain of and the N-terminal is to transcription of a in response to Ca2+ signals in cortical neurons (3Mao Z. Bonni A. Xia F. Nadal-Vicens M. Greenberg M.E. Science. 1999; 286: 785-790Crossref PubMed Scopus (446) Google Scholar). of by p38 on is for Ca2+ of activity. Although p38 not MEF2D M. L. Y. H. F. Olson E.N. R.J. Han J. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar), the of MEF2D is in by F. N. T.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). We that a protein the and only the domain similar to to by as it not HDAC5 that in the We the of of MEF2D to the DNA binding domain to expression of the that, unlike was not activated by to stimulate Ca2+ influx through synaptic NMDA receptors to activate not This that the of MEF2D is required for Ca2+ activation of MEF2D-mediated gene expression. of cAMP on Ca2+-activated conserved MADS box and MEF2 domain in the of MEF2 proteins not only with such as HDAC5 also with such as and In recruitment by the MADS domain is an important in MEF2D-mediated transcriptional activation of the by Ca2+ signals T.A. 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We the effects of cAMP on the localization of the hippocampal isoform NFAT3/c4. hippocampal neurons were with an expression for and localization by were as both nuclear and or In hippocampal neurons, was in of and with a increase in the of nuclear localization of and were to in the similar to that in neurons. when and were was to to exposure of hippocampal neurons to which to NMDA Ca2+ a nuclear of that was by of not cAMP the Ca2+-induced nuclear of in hippocampal neurons. We have shown here that an increase in intracellular cAMP the Ca2+ activation of MEF2D acts synergistically with Ca2+ to activate This activation of the transcription factors may have for many neuronal that transcriptional induced by the second long term neuronal differentiation, and neuronal long term of at hippocampal which is an of neuronal signaling cascades by both Ca2+ and cAMP 2003; PubMed Scopus Google Scholar, Neuron. Full Text Full Text PDF PubMed Scopus Google Scholar). has an where in the of a on of synaptic proteins and a that is at in the of which the the of neurons is at an increase in Ca2+ mediated by NMDA activation J. S. F. PubMed Scopus Google Scholar). The increase in intracellular Ca2+ during may cAMP levels by of Ca2+-activated PubMed Scopus Google Scholar). because the hippocampus S. S. J. 2000; PubMed Scopus Google Scholar), of receptors by the also cAMP levels during The of Ca2+ and cAMP different synaptic determine the of transcription of and Because genes are and during LTP, the of MEF2D-mediated gene expression an important for of A. Y. K. Neurosci. Lett. 1998; PubMed Scopus Google Scholar). Although a for MEF2 proteins in synaptic has not yet been serum response a transcription factor to the MADS has been implicated in hippocampal N. Shen Y. S. T. Ginty D.D. Neurosci. PubMed Scopus Google Scholar). The of MEF2D by cAMP may also have important for neuronal that in hippocampal neurons that and MEF2D activation the of Y. S. Greenberg M.E. Science. PubMed Scopus Google Scholar). activity in cerebellar granule neurons, its by and A. Gaudilliere B. Z. J. T. Y. B. Bonni A. Science. PubMed Scopus Google Scholar). the of MEF2D by cAMP may have important for during neuronal Our that MEF2D activation of which is with pro-survival is by cAMP is because cAMP has been to have effects (7Hanson Jr., M.G. Shen S. Wiemelt A.P. McMorris F.A. Barres B.A. J. Neurosci. 1998; 18: 7361-7371Crossref PubMed Google Scholar, 8Li M. Wang X. Meintzer M.K. Laessig T. Birnbaum M.J. Heidenreich K.A. Mol. Cell. Biol. 2000; 20: 9356-9363Crossref PubMed Scopus (335) Google Scholar). cAMP can S. S. Xia Z. J. Neurosci. 2003; 23: PubMed Google Scholar) that increases in intracellular cAMP inhibit the of neurotrophic factor to cortical neurons from induced by the of S. S. Xia Z. J. Neurosci. 2003; 23: PubMed Google Scholar) that, cAMP also inhibits neurotrophic transcription of a gene DNA binding for serum response factor. Because MEF2D and serum response factor belong to the family of transcription factors, it to the effects of cAMP on neurotrophic factor activation of MEF2D in cortical and hippocampal neurons of serum Our a that that, in cerebellar granule neurons, cAMP signaling in enhances gene expression mediated by MEF2 X. X. Li M. J. Mao Z. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This effect of cAMP was shown to due to a of the MEF2 isoform MEF2C, which increases its DNA binding X. X. Li M. J. Mao Z. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The identified in is conserved in a similar regulation of MEF2D by the is that are between cerebellar granule and hippocampal neurons. the types of are in different which for the Although cerebellar granule neurons to during the in high extracellular to in the of serum X. X. Li M. J. Mao Z. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), hippocampal were in the of serum for by in and both of We have shown here that the mechanisms by which cAMP inhibits the activation of MEF2D by Ca2+ signals in hippocampal neurons both its co-repressor and of the mechanisms the effects of Ca2+ and cAMP on MEF2D activity is shown in Although Ca2+ signals nuclear export of the MEF2 co-repressor cAMP inhibits its The Ca2+-dependent nuclear export of HDAC5 by kinases on and in the that are conserved in HDAC4, -5, and (reviewed in Ref. 2McKinsey T.A. Zhang C.L. Olson E.N. Trends Biochem. Sci. 2002; 27: 40-47Abstract Full Text Full Text PDF PubMed Scopus (589) Google Scholar) and with the family of The of HDAC5 nuclear export by cAMP may of the which are required for by a phosphatase or may by a kinase on distinct that nuclear In of the second it has been that activation of the by expression of in muscle results in of HDAC4 the and that is by of HDAC4 by X. Wang Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). in intracellular cAMP can to activation factors and that are directly activated by cAMP and stimulate the and J. Neurochem. 2003; PubMed Scopus Google Scholar). that HDAC4 and similar regulation by the that HDAC5 is to the by activated in neurons, to HDAC4 in cells, further In addition to inhibiting HDAC5 nuclear cAMP also antagonized Ca2+-activated nuclear of the MEF2 co-activator Ca2+-activated transcription is by cAMP in T cells, and effect of cAMP is mediated by of proteins on conserved in the N-terminal R.J. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar, C.M. P. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In the of by it for further by glycogen synthase that inhibit its nuclear by Ca2+ signals C.M. P. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In the of by its transcriptional activity in did not its subcellular localization in R.J. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar). This is in to the of nuclear in hippocampal neurons. that nuclear by cAMP both and the of effect on nuclear export by in due to levels of activity or expression of in cells. has been implicated in neuronal survival in cerebellar granule neurons, where stimuli its nuclear export Lehtinen M. T. A. Bonni A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). expression was neuronal was pro-survival of the Lehtinen M. T. A. Bonni A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This effect of in due to of MEF2 the interaction between and signaling the activity of MEF2 transcription factors, which in has for neuronal and and for the survival of different neuronal We and and for