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Gene Review

Calm1  -  calmodulin 1

Rattus norvegicus

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Disease relevance of Calm1


Psychiatry related information on Calm1


High impact information on Calm1

  • Calmodulin and Munc13 form a Ca2+ sensor/effector complex that controls short-term synaptic plasticity [11].
  • Ca2+ sensor/effector complexes consisting of calmodulin and Munc13s regulate synaptic vesicle priming and synaptic efficacy in response to a residual [Ca2+] signal and thus shape short-term plasticity characteristics during periods of sustained synaptic activity [11].
  • Furthermore, calmodulin binding to NR1 causes a 4-fold reduction in NMDA channel open probability [12].
  • One part of the calmodulin recognition element protrudes away from the catalytic domain and is potentially available for an initial interaction with calmodulin [13].
  • The structure provides a view of an intact calmodulin target and suggests that substantial structural changes will accompany kinase activation by calmodulin binding to the regulatory region [13].

Chemical compound and disease context of Calm1


Biological context of Calm1

  • We report here that the mutation of a specific calmodulin binding site in the CO region of the NR1 subunit of the NMDA receptor blocks CDI [18].
  • Recent studies have demonstrated that the calcium binding protein calmodulin directly interacts with NMDA receptors, suggesting that calmodulin may play a role in CDI [18].
  • In all cases tested, the intramolecularly disulfide bridged Ng proteins displayed dramatically attenuated CaM-binding affinity and approximately 2-3-fold weaker protein kinase C substrate phosphorylation activity [19].
  • In addition, we have identified a novel IQ type CaM binding motif within the catalytic region of PLC-delta1 that is not found in other PLC isoforms [20].
  • Here we report a novel regulatory mechanism for PLC-delta1 activation that involves direct interaction of the small GTPase Ral and the universal calcium-signaling molecule calmodulin (CaM) with PLC-delta1 [20].

Anatomical context of Calm1


Associations of Calm1 with chemical compounds

  • Neurogranin is a neural-specific, calmodulin (CaM)-binding protein that is phosphorylated by protein kinase C (PKC) within its IQ domain at serine 36 [24].
  • Nitric oxide modification of rat brain neurogranin affects its phosphorylation by protein kinase C and affinity for calmodulin [25].
  • The Ile-33 --> Gln point mutant completely inhibited and Arg-38 --> Gln and Ser-36 --> Asp point mutants reduced neurogranin/CaM interactions [24].
  • Unlike Cys(-)-, red-, and GS-NG, neither ox- nor PO(4)-NG bound to a CaM-affinity column [26].
  • These results indicate that modification of NG to form intramolecular disulfides outside the IQ domain provides an alternative mechanism for regulation of its binding affinity to CaM [26].

Physical interactions of Calm1


Enzymatic interactions of Calm1

  • CaM also failed to protect DEANO-mediated oxidation of PKC-phosphorylated Ng with or without Ca2+ [25].
  • CaM and S100 inhibited the PKM-catalyzed phosphorylation of MARCKS only in the presence of Ca2+ and addition of phosphatidylserine (PS)/dioleoylglycerol (DG) did not influence the inhibitory effect [32].
  • Calmodulin-dependent tyrosine phosphatase activity of calcineurin was observed in vitro using both immunoprecipitated and recombinant tyrosine-phosphorylated IRS-1 as substrates [33].
  • Consistent with the inhibitor specificity, the same TPH was phosphorylated by exogenous Ca2+/calmodulin-dependent protein kinase II in the presence of Ca2+ and calmodulin but not by protein kinase A (catalytic subunit) [34].
  • Both cAMP- and calmodulin-dependent kinases are proposed regulators of microtubule function by means of their ability to phosphorylate microtubule-associated protein 2(MAP 2) [35].

Co-localisations of Calm1

  • Over 60% of the plasma membrane-associated calmodulin co-localized with B-50/GAP-43 in a non-random distribution [36].

Regulatory relationships of Calm1

  • Phosphorylation of Nm or Ng by PKM was inhibited by CaM to a higher degree in the absence than in the presence of Ca2+ [32].
  • The NMDA receptor antagonist APV could partially or completely block dynorphin inhibition of CaM level and PDE activity without affecting paralysis and decrease of AC-cAMP level induced by dynorphin A (1-17) 10 min after intrathecal injection [37].
  • Also, the ET-1-, ionomycin-, and thapsigargin-induced PGHS-2 mRNA expression and protein formation was inhibited in MC pretreated with inhibitors of calcium calmodulin kinase [38].
  • Calmodulin inhibitors (W7 and calmidazolium) and tyrosine kinase inhibitors (genistein and ST638) completely blocked ERK activation by Ang II and A23187 [39].
  • Recently, using rat hippocampal slices, we found that BDNF induces activation of calcium/calmodulin-dependent protein kinase 2 (CaMKII), a critical mediator of synaptic plasticity [30].

Other interactions of Calm1

  • Thus, the Ral-CaM complex defines a multifaceted regulatory mechanism for PLC-delta1 activation [20].
  • We conclude that in addition to its direct effects on single channel activity, calcineurin regulates the effects of calmodulin on NMDA receptor activity [40].
  • The CaM-mediated inhibition of Nm or Ng phosphorylation by PKM was also not affected by PS/DG either with or without Ca2+ [32].
  • Protease-activated catalytic fragment of PKC (PKM) was used to determine the effects of Ca2+ and phospholipid on the CaM and S100-mediated inhibition of PKC substrate phosphorylation [32].
  • The present study examined the activation of CaM-kinase II (calcium/calmodulin-dependent protein kinase II) in CA1 and CA3 areas after glutamate or potassium stimulation [41].

Analytical, diagnostic and therapeutic context of Calm1


  1. Disruption of the EF-2 kinase/Hsp90 protein complex: a possible mechanism to inhibit glioblastoma by geldanamycin. Yang, J., Yang, J.M., Iannone, M., Shih, W.J., Lin, Y., Hait, W.N. Cancer Res. (2001) [Pubmed]
  2. Differential and time-dependent changes in gene expression for type II calcium/calmodulin-dependent protein kinase, 67 kDa glutamic acid decarboxylase, and glutamate receptor subunits in tetanus toxin-induced focal epilepsy. Liang, F., Jones, E.G. J. Neurosci. (1997) [Pubmed]
  3. N-methyl D-aspartate receptor-mediated bidirectional control of extracellular signal-regulated kinase activity in cortical neuronal cultures. Chandler, L.J., Sutton, G., Dorairaj, N.R., Norwood, D. J. Biol. Chem. (2001) [Pubmed]
  4. Neuronal protection and preservation of calcium/calmodulin-dependent protein kinase II and protein kinase C activity by dextrorphan treatment in global ischemia. Aronowski, J., Waxham, M.N., Grotta, J.C. J. Cereb. Blood Flow Metab. (1993) [Pubmed]
  5. Status epilepticus results in an N-methyl-D-aspartate receptor-dependent inhibition of Ca2+/calmodulin-dependent kinase II activity in the rat. Kochan, L.D., Churn, S.B., Omojokun, O., Rice, A., DeLorenzo, R.J. Neuroscience (2000) [Pubmed]
  6. Neuropeptide Y treatment and food deprivation increase cyclic AMP response element-binding in rat hypothalamus. Sheriff, S., Chance, W.T., Fischer, J.E., Balasubramaniam, A. Mol. Pharmacol. (1997) [Pubmed]
  7. Decreases in calmodulin binding proteins and calmodulin dependent protein phosphorylation in the medial preoptic area at the onset of maternal behavior in the rat. O'Day, D.H., Lydan, M., Watchus, J., Fleming, A.S. J. Neurosci. Res. (2001) [Pubmed]
  8. Down-regulation of striatin, a neuronal calmodulin-binding protein, impairs rat locomotor activity. Bartoli, M., Ternaux, J.P., Forni, C., Portalier, P., Salin, P., Amalric, M., Monneron, A. J. Neurobiol. (1999) [Pubmed]
  9. The effect of prolonged imipramine and electroconvulsive shock treatment on calcium/calmodulin-dependent protein kinase II in the hippocampus of rat brain. Pilc, A., Branski, P., Palucha, A., Aronowski, J. Neuropharmacology (1999) [Pubmed]
  10. Water deprivation upregulates the three calmodulin genes in exclusively the supraoptic nucleus of the rat brain. Palfi, A., Gulya, K. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  11. Calmodulin and Munc13 form a Ca2+ sensor/effector complex that controls short-term synaptic plasticity. Junge, H.J., Rhee, J.S., Jahn, O., Varoqueaux, F., Spiess, J., Waxham, M.N., Rosenmund, C., Brose, N. Cell (2004) [Pubmed]
  12. Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Ehlers, M.D., Zhang, S., Bernhadt, J.P., Huganir, R.L. Cell (1996) [Pubmed]
  13. Structural basis for the autoinhibition of calcium/calmodulin-dependent protein kinase I. Goldberg, J., Nairn, A.C., Kuriyan, J. Cell (1996) [Pubmed]
  14. Calcium/calmodulin-dependent protein kinase II (CaMKII), through NMDA receptors and L-Voltage-gated channels, modulates the serine phosphorylation of GluR6 during cerebral ischemia and early reperfusion period in rat hippocampus. Hao, Z.B., Pei, D.S., Guan, Q.H., Zhang, G.Y. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  15. Chronic inhibition of Ca(2+)/calmodulin kinase II activity in the pilocarpine model of epilepsy. Churn, S.B., Kochan, L.D., DeLorenzo, R.J. Brain Res. (2000) [Pubmed]
  16. Phosphorylation of tyrosine hydroxylase by calmodulin-dependent multiprotein kinase. Vulliet, P.R., Woodgett, J.R., Cohen, P. J. Biol. Chem. (1984) [Pubmed]
  17. Essential role of methionine residues in calmodulin binding to Bordetella pertussis adenylate cyclase, as probed by selective oxidation and repair by the peptide methionine sulfoxide reductases. Vougier, S., Mary, J., Dautin, N., Vinh, J., Friguet, B., Ladant, D. J. Biol. Chem. (2004) [Pubmed]
  18. Calmodulin mediates calcium-dependent inactivation of N-methyl-D-aspartate receptors. Zhang, S., Ehlers, M.D., Bernhardt, J.P., Su, C.T., Huganir, R.L. Neuron (1998) [Pubmed]
  19. Nitric oxide modification of rat brain neurogranin. Identification of the cysteine residues involved in intramolecular disulfide bridge formation using site-directed mutagenesis. Mahoney, C.W., Pak, J.H., Huang, K.P. J. Biol. Chem. (1996) [Pubmed]
  20. Regulation of phospholipase C-delta1 through direct interactions with the small GTPase Ral and calmodulin. Sidhu, R.S., Clough, R.R., Bhullar, R.P. J. Biol. Chem. (2005) [Pubmed]
  21. Ca2+-dependent and -independent mechanisms of calmodulin nuclear translocation. Thorogate, R., Török, K. J. Cell. Sci. (2004) [Pubmed]
  22. Volume-regulated anion conductance in cultured rat cerebral astrocytes requires calmodulin activity. Olson, J.E., Li, G.Z., Wang, L., Lu, L. Glia (2004) [Pubmed]
  23. Localization of the protein kinase C phosphorylation/calmodulin-binding substrate RC3 in dendritic spines of neostriatal neurons. Watson, J.B., Sutcliffe, J.G., Fisher, R.S. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  24. Interactions between neurogranin and calmodulin in vivo. Prichard, L., Deloulme, J.C., Storm, D.R. J. Biol. Chem. (1999) [Pubmed]
  25. Nitric oxide modification of rat brain neurogranin affects its phosphorylation by protein kinase C and affinity for calmodulin. Sheu, F.S., Mahoney, C.W., Seki, K., Huang, K.P. J. Biol. Chem. (1996) [Pubmed]
  26. Calcium-sensitive interaction between calmodulin and modified forms of rat brain neurogranin/RC3. Huang, K.P., Huang, F.L., Li, J., Schuck, P., McPhie, P. Biochemistry (2000) [Pubmed]
  27. Apo-calmodulin binds with its C-terminal domain to the N-methyl-D-aspartate receptor NR1 C0 region. Akyol, Z., Bartos, J.A., Merrill, M.A., Faga, L.A., Jaren, O.R., Shea, M.A., Hell, J.W. J. Biol. Chem. (2004) [Pubmed]
  28. Phosphorylation of myristoylated alanine-rich protein kinase C substrate by mitogen-activated protein kinase in cultured rat hippocampal neurons following stimulation of glutamate receptors. Ohmitsu, M., Fukunaga, K., Yamamoto, H., Miyamoto, E. J. Biol. Chem. (1999) [Pubmed]
  29. Connexin 32 of gap junctions contains two cytoplasmic calmodulin-binding domains. Török, K., Stauffer, K., Evans, W.H. Biochem. J. (1997) [Pubmed]
  30. A calcium/calmodulin kinase pathway connects brain-derived neurotrophic factor to the cyclic AMP-responsive transcription factor in the rat hippocampus. Blanquet, P.R., Mariani, J., Derer, P. Neuroscience (2003) [Pubmed]
  31. Relationship of genes encoding Ca2+/calmodulin-dependent protein kinase Gr and calspermin: a gene within a gene. Ohmstede, C.A., Bland, M.M., Merrill, B.M., Sahyoun, N. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  32. Differential responses of protein kinase C substrates (MARCKS, neuromodulin, and neurogranin) phosphorylation to calmodulin and S100. Sheu, F.S., Huang, F.L., Huang, K.P. Arch. Biochem. Biophys. (1995) [Pubmed]
  33. Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) by oxidant stress in cerebellar granule neurons: modulation by N-methyl-D-aspartate through calcineurin activity. Hallak, H., Ramadan, B., Rubin, R. J. Neurochem. (2001) [Pubmed]
  34. Proteasome-driven turnover of tryptophan hydroxylase is triggered by phosphorylation in RBL2H3 cells, a serotonin producing mast cell line. Iida, Y., Sawabe, K., Kojima, M., Oguro, K., Nakanishi, N., Hasegawa, H. Eur. J. Biochem. (2002) [Pubmed]
  35. Separation of endogenous calmodulin- and cAMP-dependent kinases from microtubule preparations. Vallano, M.L., Goldenring, J.R., Buckholz, T.M., Larson, R.E., DeLorenzo, R.J. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  36. Ultrastructural co-localization of calmodulin and B-50/growth-associated protein-43 at the plasma membrane of proximal unmyelinated axon shafts studied in the model of the regenerating rat sciatic nerve. Verkade, P., Schrama, L.H., Verkleij, A.J., Gispen, W.H., Oestreicher, A.B. Neuroscience (1997) [Pubmed]
  37. Effects of dynorphin A (1-17) on motor function and spinal intracellular messenger systems in rat. Zhang, Z., Li, F., Ren, M., Liu, J. Chin. Med. Sci. J. (1996) [Pubmed]
  38. Calcium-regulated protein tyrosine phosphorylation is required for endothelin-1 to induce prostaglandin endoperoxide synthase-2 mRNA expression and protein synthesis in mesangial cells. Coroneos, E.J., Kester, M., Maclouf, J., Thomas, P., Dunn, M.J. J. Am. Soc. Nephrol. (1997) [Pubmed]
  39. Role of calcium-sensitive tyrosine kinase Pyk2/CAKbeta/RAFTK in angiotensin II induced Ras/ERK signaling. Murasawa, S., Mori, Y., Nozawa, Y., Masaki, H., Maruyama, K., Tsutsumi, Y., Moriguchi, Y., Shibasaki, Y., Tanaka, Y., Iwasaka, T., Inada, M., Matsubara, H. Hypertension (1998) [Pubmed]
  40. Inhibitory interactions of calcineurin (phosphatase 2B) and calmodulin on rat hippocampal NMDA receptors. Rycroft, B.K., Gibb, A.J. Neuropharmacology (2004) [Pubmed]
  41. The activation of calcium/calmodulin-dependent protein kinase II after glutamate or potassium stimulation in hippocampal slices. Tan, S.E., Chen, S.S. Brain Res. Bull. (1997) [Pubmed]
  42. Characterization of a 7.5-kDa protein kinase C substrate (RC3 protein, neurogranin) from rat brain. Huang, K.P., Huang, F.L., Chen, H.C. Arch. Biochem. Biophys. (1993) [Pubmed]
  43. The identification and characterization of a noncontinuous calmodulin-binding site in noninactivating voltage-dependent KCNQ potassium channels. Yus-Najera, E., Santana-Castro, I., Villarroel, A. J. Biol. Chem. (2002) [Pubmed]
  44. Molecular cloning of calmodulin mRNA species which are preferentially expressed in neurons in the rat brain. Ni, B., Rush, S., Gurd, J.W., Brown, I.R. Brain Res. Mol. Brain Res. (1992) [Pubmed]
  45. Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: electrophysiological and molecular studies. Alzoubi, K.H., Gerges, N.Z., Alkadhi, K.A. Exp. Neurol. (2005) [Pubmed]
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