Phosphorylation of CBP Mediates Transcriptional Activation by Neural Activity and CaM Kinase IV

Type I adenylyl cyclase is a neurospecific enzyme that is stimulated by Ca2+ and calmodulin (CaM). This enzyme couples the Ca2+ and cyclic AMP (cAMP) regulatory systems in neurons, and it may play an important role for some forms of synaptic plasticity. Mutant mice lacking type I adenylyl cyclase show deficiencies in spatial memory and altered long-term potentiation (Z. Wu, S. A. Thomas, Z. Xia, E. C. Villacres, R. D. Palmiter, and D. R. Storm, Proc. Natl. Acad. Sci. USA 92:220-224, 1995). Although type I adenylyl cyclase is synergistically stimulated by Ca2+ and G-protein-coupled receptors in vivo, very little is known about mechanisms for inhibition of the enzyme. Here, we report that type I adenylyl cyclase is inhibited by CaM kinase IV in vivo. Expression of constitutively active or wild-type CaM kinase IV inhibited Ca2+ stimulation of adenylyl cyclase activity without affecting basal or forskolin-stimulated activity. Type I adenylyl cyclase has two CaM kinase IV consensus phosphorylation sequences near its CaM binding domain at Ser-545 and Ser-552. Conversion of either serine to alanine by mutagenesis abolished CaM kinase IV inhibition of adenylyl cyclase. This suggests that the activity of this enzyme may be directly inhibited by CaM kinase IV phosphorylation. Type VIII adenylyl cyclase, another enzyme stimulated by CaM, was not inhibited by CaM kinase II or IV. We propose that CaM kinase IV may function as a negative feedback regulator of type I adenylyl cyclase and that CaM kinases may regulate cAMP levels in some cells.

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Brain tissue energy dependence of CaM kinase IV cascade activation during hypoxia in the cerebral cortex of newborn piglets

Neuroscience Letters ◽

10.1016/j.neulet.2011.01.017 ◽

2011 ◽

Vol 491 (2) ◽

pp. 113-117 ◽

Cited By ~ 8

Author(s):

Maria Delivoria-Papadopoulos ◽

Qazi M. Ashraf ◽

Om Prakash Mishra

Keyword(s):

Cerebral Cortex ◽

Brain Tissue ◽

Energy Dependence ◽

Cam Kinase ◽

Newborn Piglets ◽

Cam Kinase Iv

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The effect of hypocapnia (PaCO2 27 mmHg) on CaM kinase IV activity, Bax/Bcl-2 protein expression and DNA fragmentation in the cerebral cortex of newborn piglets

Neuroscience Letters ◽

10.1016/s0304-3940(03)01042-5 ◽

2003 ◽

Author(s):

K Fritz

Keyword(s):

Cerebral Cortex ◽

Protein Expression ◽

Dna Fragmentation ◽

Cam Kinase ◽

Newborn Piglets ◽

Cam Kinase Iv

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Reduced CREB phosphorylation after chronic lithium treatment is associated with down-regulation of CaM kinase IV in rat hippocampus

The International Journal of Neuropsychopharmacology ◽

10.1017/s1461145706007140 ◽

2006 ◽

Vol 10 (04) ◽

pp. 491 ◽

Cited By ~ 15

Author(s):

Daniela Tardito ◽

Ettore Tiraboschi ◽

Jiro Kasahara ◽

Giorgio Racagni ◽

Maurizio Popoli

Keyword(s):

Lithium Treatment ◽

Rat Hippocampus ◽

Cam Kinase ◽

Down Regulation ◽

Creb Phosphorylation ◽

Cam Kinase Iv

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Signaling through CD5 Activates a Pathway Involving Phosphatidylinositol 3-Kinase, Vav, and Rac1 in Human Mature T Lymphocytes

Molecular and Cellular Biology ◽

10.1128/mcb.18.3.1725 ◽

1998 ◽

Vol 18 (3) ◽

pp. 1725-1735 ◽

Cited By ~ 50

Author(s):

Sonja I. Gringhuis ◽

Lou F. M. H. de Leij ◽

Paul J. Coffer ◽

Edo Vellenga

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Signaling Pathway ◽

Tyrosine Phosphorylation ◽

Interleukin 2 ◽

Dominant Negative ◽

Induced Response ◽

Cam Kinase ◽

Cam Kinase Iv ◽

Constitutively Active

ABSTRACT CD5 acts as a coreceptor on T lymphocytes and plays an important role in T-cell signaling and T-cell–B-cell interactions. Costimulation of T lymphocytes with anti-CD5 antibodies results in an increase of the intracellular Ca2+ levels, and subsequently in the activation of Ca2+/calmodulin-dependent (CaM) kinase type IV. In the present study, we have characterized the initial signaling pathway induced by anti-CD5 costimulation. The activation of phosphatidylinositol (PI) 3-kinase through tyrosine phosphorylation of its p85 subunit is a proximal event in the CD5-signaling pathway and leads to the activation of the lipid kinase activity of the p110 subunit. The PI 3-kinase inhibitors wortmannin and LY294002 inhibit the CD5-induced response as assessed in interleukin-2 (IL-2) secretion experiments. The expression of an inactivated Rac1 mutant (Rac1 · N17) in T lymphocytes transfected with an IL-2 promoter-driven reporter construct also abrogates the response to CD5 costimulation, while the expression of a constitutively active Rac1 mutant (Rac1-V12) completely replaces the CD5 costimulatory signal. The Rac1-specific guanine nucleotide exchange factor Vav is heavily phosphorylated on tyrosine residues upon CD5 costimulation, which is a prerequisite for its activation. A role for Vav in the CD5-induced signaling pathway is further supported by the findings that the expression of a dominant negative Vav mutant (Vav-C) completely abolishes the response to CD5 costimulation while the expression of a constitutively active Vav mutant [Vav(Δ1–65)] makes the CD5 costimulation signal superfluous. Wortmannin is unable to block the Vav(Δ1–65)- or Rac1 · V12-induced signals, indicating that both Vav and Rac1 function downstream from PI 3-kinase. Vav and Rac1 both act upstream from the CD5-induced activation of CaM kinase IV, since KN-62, an inhibitor of CaM kinases, and a dominant negative CaM kinase IV mutant block the Vav(Δ1–65)-and Rac1 · V12-mediated signals. We propose a model for the CD5-induced signaling pathway in which the PI 3-kinase lipid products, together with tyrosine phosphorylation, activate Vav, resulting in the activation of Rac1 by the Vav-mediated exchange of GDP for GTP.

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