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Gene Review

Camk2d  -  calcium/calmodulin-dependent protein...

Rattus norvegicus

Synonyms: CAMK1, CaM kinase II subunit delta, CaMK-II subunit delta, Calcium/calmodulin-dependent protein kinase type II subunit delta, Camk2, ...
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Disease relevance of Camk2d


Psychiatry related information on Camk2d


High impact information on Camk2d

  • Calcium/calmodulin-stimulated autophosphorylation of a prominent brain calmodulin-dependent protein kinase (Type II CaM kinase) produces dramatic changes in its enzymatic activity [7].
  • Activation of the multifunctional Ca(2+)-calmodulin-dependent protein kinase (CaM kinase) was evoked by stimulation of either NMDA receptors or L-type Ca2+ channels; however, activation of CaM kinase appeared to be critical only for propagating the L-type Ca2+ channel signal to the nucleus [8].
  • These findings reveal central roles for HDACs in chromatin remodeling during myogenesis and as intranuclear targets for signaling pathways controlled by IGF and CaM kinase [9].
  • We show that secreted insulin acts via beta-cell insulin receptors and up-regulates insulin gene transcription by signaling through the IRS-2/PI-3 kinase/p70 s6k and CaM kinase pathways [10].
  • Here we show that synapsin Ia's dispersion rate tracks the synaptic vesicle pool turnover rate linearly over the range 5-20 Hz and that the molecular basis for this lies in regulation at both the calcium-calmodulin-dependent kinase (CaM kinase) and the mitogen-activated protein (MAP) kinase/calcineurin sites [11].

Chemical compound and disease context of Camk2d


Biological context of Camk2d

  • These results suggest that increased phosphorylation of CREB protein may contribute to central sensitization following acute peripheral noxious stimuli, and the effect may be regulated through the activation of CaM kinase cascades [17].
  • The deduced amino acid sequence that we have obtained from the new CaM kinase II isoforms indicates a molecular organization which could make the design of subtype-specific inhibitory drugs for CaM kinase II possible [18].
  • A constitutively active mutant of CaM kinase IV, but not of CaM kinase II, leads to activation of the promoter in the absence of extracellular stimuli, and partially occludes calcium-dependent transactivation [19].
  • We predicted that the 8-petal molecules and 10-petal molecules were octamers and decamers of CaM kinase II subunits, respectively, each assembled with the association domains of subunits gathered in the center, and the catalytic domains in the peripheral particles [20].
  • Intracellular targeting may enable protein kinases with broad substrate-specificities, such as multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) to achieve a selectivity of action in vivo [21].

Anatomical context of Camk2d


Associations of Camk2d with chemical compounds

  • The present study was designed to investigate the role of calcium/camodulin protein dependent protein kinase II (CaM kinase II) in the regulation of phosphorylation of CREB after capsaicin injection [17].
  • 4. Investigation of the potential downstream mediators in the G(alpha i) NSC channel pathway revealed that activation of the cation conductance was unaffected by treatment of RPE cells with the selective protein kinase C inhibitor GF 109203X (3 microM) or the selective CaM kinase II inhibitor KN-93 (50 microM) [26].
  • Binding of antibodies to the enzyme molecules suggested that molecules with 8 and 10 peripheral particles were homopolymers composed only of beta subunit and of alpha subunit, respectively, specifying that CaM kinase II consists of homopolymer of either alpha or beta subunits [20].
  • The other is the inositol trisphosphate (IP3)/Ca2+ pathway and a major downstream kinase which is activated is Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) [27].
  • These results suggest that arachidonate and its metabolites may modulate synaptic function through the inhibition of CaM-kinase II-dependent protein phosphorylation [28].

Physical interactions of Camk2d

  • By using 125I-calmodulin overlay techniques and sodium dodecyl sulfate-polyacrylamide gel electrophoresis we found that phosphorylated 50K and 60K CaM-kinase II polypeptides bound more calmodulin (50-70%) than did unphosphorylated kinase polypeptides [29].

Enzymatic interactions of Camk2d

  • In parallel fashion to its activation, CaM kinase IV is phosphorylated in a CaM kinase Ia kinase-, Ca(2+)-CaM-, and MgATP-dependent manner [30].
  • These data provide evidence that MAP-2 is phosphorylated by CaM kinase II in the pancreatic beta-cell in situ, and that this event may provide an important link in the mediation of Ca2+-dependent insulin secretion [31].
  • The CaM-kinase II activity in phosphorylated SJs was indistinguishable from control SJs at saturating calmodulin concentrations (300-1,000 nM) [29].

Co-localisations of Camk2d


Regulatory relationships of Camk2d

  • Furthermore, we demonstrate that pretreatment with KN-93 or a CaM kinase II inhibitor peptide inhibits Ca(2+)-dependent PYK2 activation and EGF receptor tyrosine phosphorylation in response to ionomycin, ATP, and platelet-derived growth factor but has no effect on phorbol 12,13-dibutyrate- or EGF-induced responses [33].
  • We have used these antibodies to demonstrate that serine 831 is specifically phosphorylated by CaM kinase II in transfected cells expressing GluR1 as well as in hippocampal slice preparations [34].
  • Similar to CaM kinases II and IV, CaM kinase I was essentially activated by stimulation with the NMDA receptor [35].
  • Autophosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaM-kinase) induces a more than 1000-fold increase in calmodulin (CaM)-binding affinity by dramatically decreasing the off-rate for CaM [36].
  • In addition, CaM kinase I was activated in a lower concentration of glutamate than that of CaM kinase IV [35].

Other interactions of Camk2d

  • Calcium/calmodulin dependent protein kinase II (CaM kinase II) seems to act as an important regulator of intracellular signal transmission [37].
  • CBP-mediated transcription is stimulus strength-dependent and can be induced by activation of CaM kinase II, CaM kinase IV, and protein kinase A, but not by activation of the Ras-MAP kinase pathway [38].
  • Treatment of cells with KN-93 did not antagonize the ability of ionomycin to mobilize intracellular Ca2+ but prevented CaM kinase II and ERK1/2 activation with almost identical potencies [39].
  • Transient expression of wild-type delta 2 CaM kinase II in COS-7 cells resulted in increased ERK2 activity, whereas coexpression of wild-type and a kinase-negative mutant resulted in a diminution of this response [39].
  • Nevertheless, the percentage of calcium-independent CaM-kinase II activity in the CA3 area was suppressed by EGTA, nitrendipine, KN-62, staurosporin, or H-89, indicating that the activity of CaM-kinase II in the CA3 area was independent of NMDA receptor activation [40].

Analytical, diagnostic and therapeutic context of Camk2d

  • In the present investigation, the subcellular and regional distribution of CaM kinase II has been studied by light and electron microscopic immunocytochemistry using an antibody that recognizes the Mr 50,000 and 60,000/58,000 subunits of the enzyme [41].
  • Western blot analysis revealed that the microsomes contain the alpha isoform of CaM kinase II but do not contain CaM [42].
  • The association of soluble Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) with postsynaptic densities (PSDs) was determined by activity assay, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunoblotting of the enzyme [43].
  • The subunit composition of CaM kinase II holoenzymes was analyzed by immunoprecipitation with subunit-specific monoclonal antibodies [44].
  • Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II) autophosphorylated under limiting conditions (7 microM [gamma-32P]ATP, 500 microM magnesium acetate, 4 degrees C) was analyzed by CNBr cleavage and peptide mapping to determine the site of autophosphorylation that brings about transition of the kinase to the Ca2+-independent form [45].


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  8. Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. Bading, H., Ginty, D.D., Greenberg, M.E. Science (1993) [Pubmed]
  9. Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Lu, J., McKinsey, T.A., Zhang, C.L., Olson, E.N. Mol. Cell (2000) [Pubmed]
  10. Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Leibiger, I.B., Leibiger, B., Moede, T., Berggren, P.O. Mol. Cell (1998) [Pubmed]
  11. Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies. Chi, P., Greengard, P., Ryan, T.A. Neuron (2003) [Pubmed]
  12. Excitotoxicity affects membrane potential and calmodulin kinase II activity in cultured rat cortical neurons. Churn, S.B., Sombati, S., Taft, W.C., DeLorenzo, R.J. Stroke (1993) [Pubmed]
  13. Receptor subtype and intracellular signal transduction pathway associated with situs inversus induced by alpha 1 adrenergic stimulation in rat embryos. Fujinaga, M., Hoffman, B.B., Baden, J.M. Dev. Biol. (1994) [Pubmed]
  14. Modulation of CaM kinase II activity is coincident with induction of status epilepticus in the rat pilocarpine model. Singleton, M.W., Holbert, W.H., Lee, A.T., Bracey, J.M., Churn, S.B. Epilepsia (2005) [Pubmed]
  15. Expression of the alpha and beta subunits of Ca2+/calmodulin kinase II in the cerebellum of jaundiced Gunn rats during development: a quantitative light microscopic analysis. Conlee, J.W., Shapiro, S.M., Churn, S.B. Acta Neuropathol. (2000) [Pubmed]
  16. Functional significance of activation of calcium/calmodulin-dependent protein kinase II in angiotensin II--induced vascular hyperplasia and hypertension. Muthalif, M.M., Karzoun, N.A., Benter, I.F., Gaber, L., Ljuca, F., Uddin, M.R., Khandekar, Z., Estes, A., Malik, K.U. Hypertension (2002) [Pubmed]
  17. Calcium/calmodulin dependent protein kinase II regulates the phosphorylation of cyclic AMP-responsive element-binding protein of spinal cord in rats following noxious stimulation. Fang, L., Wu, J., Zhang, X., Lin, Q., Willis, W.D. Neurosci. Lett. (2005) [Pubmed]
  18. Novel and uncommon isoforms of the calcium sensing enzyme calcium/calmodulin dependent protein kinase II in heart tissue. Mayer, P., Möhlig, M., Idlibe, D., Pfeiffer, A. Basic Res. Cardiol. (1995) [Pubmed]
  19. Identification of a signaling pathway involved in calcium regulation of BDNF expression. Shieh, P.B., Hu, S.C., Bobb, K., Timmusk, T., Ghosh, A. Neuron (1998) [Pubmed]
  20. Structural features of Ca2+/calmodulin-dependent protein kinase II revealed by electron microscopy. Kanaseki, T., Ikeuchi, Y., Sugiura, H., Yamauchi, T. J. Cell Biol. (1991) [Pubmed]
  21. Alternative splicing introduces a nuclear localization signal that targets multifunctional CaM kinase to the nucleus. Srinivasan, M., Edman, C.F., Schulman, H. J. Cell Biol. (1994) [Pubmed]
  22. CaM kinase IIdeltaC phosphorylation of 14-3-3beta in vascular smooth muscle cells: activation of class II HDAC repression. Ellis, J.J., Valencia, T.G., Zeng, H., Roberts, L.D., Deaton, R.A., Grant, S.R. Mol. Cell. Biochem. (2003) [Pubmed]
  23. Ca2+/calmodulin-dependent protein kinase II is phosphorylated by protein kinase C in vitro. Waxham, M.N., Aronowski, J. Biochemistry (1993) [Pubmed]
  24. Activation of multifunctional Ca2+/calmodulin-dependent kinase in intact hippocampal slices. Ocorr, K.A., Schulman, H. Neuron (1991) [Pubmed]
  25. Identification of calmodulin-dependent protein kinase III and its major Mr 100,000 substrate in mammalian tissues. Nairn, A.C., Bhagat, B., Palfrey, H.C. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  26. Activation of a nonspecific cation current in rat cultured retinal pigment epithelial cells: involvement of a G(alpha i) subunit protein and the mitogen-activated protein kinase signalling pathway. Ryan, J.S., Kelly, M.E. Br. J. Pharmacol. (1998) [Pubmed]
  27. Differential targeting of protein kinase C and CaM kinase II signalings to vimentin. Ogawara, M., Inagaki, N., Tsujimura, K., Takai, Y., Sekimata, M., Ha, M.H., Imajoh-Ohmi, S., Hirai, S., Ohno, S., Sugiura, H. J. Cell Biol. (1995) [Pubmed]
  28. Inhibition of Ca2+/calmodulin-dependent protein kinase II by arachidonic acid and its metabolites. Piomelli, D., Wang, J.K., Sihra, T.S., Nairn, A.C., Czernik, A.J., Greengard, P. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
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  30. Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation. Selbert, M.A., Anderson, K.A., Huang, Q.H., Goldstein, E.G., Means, A.R., Edelman, A.M. J. Biol. Chem. (1995) [Pubmed]
  31. Calcium-stimulated phosphorylation of MAP-2 in pancreatic betaTC3-cells is mediated by Ca2+/calmodulin-dependent kinase II. Krueger, K.A., Bhatt, H., Landt, M., Easom, R.A. J. Biol. Chem. (1997) [Pubmed]
  32. Cellular localization of calmodulin-dependent protein kinases I and II to A-cells and D-cells of the endocrine pancreas. Matovcik, L.M., Nairn, A.C., Gorelick, F.S. J. Histochem. Cytochem. (1998) [Pubmed]
  33. CaM kinase II-dependent activation of tyrosine kinases and ERK1/2 in vascular smooth muscle. Ginnan, R., Singer, H.A. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  34. Phosphorylation of the alpha-amino-3-hydroxy-5-methylisoxazole4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II. Mammen, A.L., Kameyama, K., Roche, K.W., Huganir, R.L. J. Biol. Chem. (1997) [Pubmed]
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  38. Regulation of CBP-mediated transcription by neuronal calcium signaling. Hu, S.C., Chrivia, J., Ghosh, A. Neuron (1999) [Pubmed]
  39. A role for Ca2+/calmodulin-dependent protein kinase II in the mitogen-activated protein kinase signaling cascade of cultured rat aortic vascular smooth muscle cells. Abraham, S.T., Benscoter, H.A., Schworer, C.M., Singer, H.A. Circ. Res. (1997) [Pubmed]
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  42. Requirement of calmodulin-dependent protein kinase II in cyclic ADP-ribose-mediated intracellular Ca2+ mobilization. Takasawa, S., Ishida, A., Nata, K., Nakagawa, K., Noguchi, N., Tohgo, A., Kato, I., Yonekura, H., Fujisawa, H., Okamoto, H. J. Biol. Chem. (1995) [Pubmed]
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