カルモジュリン

2015年8月25日 (火) 13:03時点におけるHajimefujii (トーク | 投稿記録)による版

藤井 哉
東京大学医学系研究科神経生化学教室
DOI:10.14931/bsd.4597 原稿受付日:2015年8月7日 原稿完成日:2015年月日
担当編集委員:和田 圭司(国立研究開発法人国立精神・神経医療研究センター)

英:calmodulin

 カルモジュリンは148アミノ酸残基、分子量約16.7kDa、酸性のCa2++結合タンパク質であり、それぞれ2つのEFハンドドメインからなるN末側ドメインとC末側ドメインがリンカーでつながったダンベル様構造をしている。カルモジュリンは、酵母、植物、昆虫からヒトまで真核生物に発現しており、特に脊椎動物の中では高い保存性を示す。Ca2+と結合することで、Ca2+バッファーとして働くほか、下流のタンパク質に結合して活性などを調節し、Ca2+センサーとしてCa2+シグナル伝達の中でも非常に重要な役割を果たす。特に脳においては、Ca2+シグナル伝達をコントロールする中心的な役割を担い、神経突起形成、軸索伸展、シナプス形成、シナプス可塑性、記憶・学習など様々な機能に関わる。

カルモジュリン
3CLN.pdb
カルモジュリンEF-handの結晶構造[1]
Identifiers
Symbol efhand
Pfam PF00036
InterPro IPR002048
PROSITE PDOC00018
SCOP 1osa
SUPERFAMILY 1osa
OPM protein 1djx
CDD cd00051
Calmodulin 1
Identifiers
Symbols CALM1; CALML2; CAMI; CPVT4; DD132; LQT14; PHKD; caM
External IDs OMIM114180 MGI88251 HomoloGene134804 GeneCards: CALM1 Gene
EC number 2.7.11.19
Orthologs
Species Human Mouse
Entrez 801 640703
Ensembl ENSG00000198668 ENSMUSG00000001175
UniProt P62158 P62204
RefSeq (mRNA) NM_001166106 NM_009790
RefSeq (protein) NP_008819 NP_033920
Location (UCSC) Chr 14:
90.4 – 90.41 Mb
Chr 12:
101.44 – 101.45 Mb
PubMed search [1] [2]
Calmodulin 2
Identifiers
Symbols CALM2; CAMII; LQT15; PHKD; PHKD2; caM
External IDs OMIM114182 MGI103250 HomoloGene134804 GeneCards: CALM2 Gene
EC number 2.7.11.19
Orthologs
Species Human Mouse
Entrez 805 640703
Ensembl ENSG00000143933 ENSMUSG00000036438
UniProt P62158 P62204
RefSeq (mRNA) NM_001305624 NM_007589
RefSeq (protein) NP_001292553 NP_031615
Location (UCSC) Chr 2:
47.16 – 47.18 Mb
Chr 17:
87.83 – 87.85 Mb
PubMed search [3] [4]
Calmodulin 3
Identifiers
Symbols CALM3; HEL-S-72; PHKD; PHKD3
External IDs OMIM114183 MGI103249 HomoloGene134804 GeneCards: CALM3 Gene
EC number 2.7.11.19
Orthologs
Species Human Mouse
Entrez 808 640703
Ensembl ENSG00000160014 ENSMUSG00000019370
UniProt P62158 P62204
RefSeq (mRNA) NM_005184 NM_007590
RefSeq (protein) NP_005175 NP_031616
Location (UCSC) Chr 19:
46.6 – 46.61 Mb
Chr 7:
17.5 – 17.51 Mb
PubMed search [5] [6]

発見

 1970年、Kakiuchiらは、ラット抽出物中の環状ヌクレオチドフォスフォジエステラーゼ活性がCa2+により制御されることを報告し[2]、このCa2+依存性を担う調節因子を見出した[3][4]。また、同じ1970年に独立してCheungは環状ヌクレオチドフォスフォジエステラーゼの活性が精製の過程で減弱することから、精製の過程で分離される分画より活性化因子を発見し報告した[5]

 1973年にTeoとWangらはウシの心臓からこの活性化因子を精製し[6]、これらの別々に発見された因子の正体が同一のCa2+結合タンパク質であることを示した[7][8]

 その後、トロポニンCに特性が類似したタンパク質であることが示され[9] [10]、アミノ酸配列が決定され[11]、分光学的解析によってCa2+結合に伴って構造が変化することが示された[12] [13] [14]。その呼び名は研究グループによって、activator protein, modulator protein, Ca2+dependent regulator protein(CDR)、Phosphodiesterase Activating Factor(PAF)などさまざまに呼ばれたが、1970年代末にcalmodulinという名称が付けられた[15][16]

構造

 カルモジュリンは148残基のアミノ酸からなる、分子量約16.7kDaのタンパク質である。1985年にCa2+存在下のウシ由来カルモジュリンのX線結晶構造が解かれ、原子レベルでの構造が明らかになった[17]。Ca2+と結合する4つのヘリックス・ループ・ヘリックス構造のEFハンドモチーフを持ち、2つずつがそれぞれペアとなって球状のN末側ドメイン、C末側ドメインを形成し、その間をリンカーがつながったダンベル様の構造をしている。それぞれの球状のドメインの大きさは約25×20×20 Åであり、分子全体としては長軸が約65 Åの長さである[17]

機能

 カルモジュリンは脳内で10~100 µmol/lの濃度で発現しており[18]、細胞内で上昇したCa2+と結合し、Ca2+バッファーとして働くのに加え、様々なカルモジュリン結合タンパク質と結合して生理機能を発揮する(表1)。  カルモジュリンの主要な機能は、細胞内のCa2+濃度の変化を感知し、カルモジュリン結合タンパクの機能制御を通じて、細胞機能を制御(活性化、抑制)することであり、その具体的な効果はターゲットとなる下流のタンパク質によって様々に異なる。カルモジュリン結合タンパク質の多くはCa2+依存性がありCa2+/カルモジュリンと結合するが、Ca2+と結合していないカルモジュリンと結合するタンパク質や、Ca2+非依存的に結合するタンパク質も存在する。

 Ca2+に対する親和性の違いから、C末側ドメインはN末側ドメインに比べCa2+に対する親和性が高く、in vitroでトリプシン処理により得られたN末側/C末側ドメインのCa2+親和性をpH7.5, 100mM KCl, 25℃の条件下で測定した場合には、それぞれ1.5~100μM、0.4~10μMである[19]。Ca2+依存的な結合の場合、カルモジュリンがCa2+と結合することで、疎水性領域が露出し、ターゲットとなるタンパク質のカルモジュリン結合ドメインにある疎水性のアミノ酸残基と相互作用する。この疎水性アミノ酸残基の位置によって、1-14モチーフ(ミオシン軽鎖キナーゼmyosin light-chain kinase, MLCK)、カルシニューリンCa2+/カルモジュリン依存性タンパク質キナーゼIVCaMKIV)、一酸化窒素合成酵素NOS))、1-10モチーフ(Ca2+/カルモジュリン依存性タンパク質キナーゼIICaMKII)、シナプシン熱ショックタンパク質70/90)、1-16モチーフ(Ca2+/カルモジュリン依存性タンパク質キナーゼキナーゼ, CaMKK)などに分類される[20][21][22]

 また、Ca2+非依存的な結合タンパク質は、IQモチーフ(IQXXXRGXXXR)を持つことが多い。

表1. カルモジュリン結合タンパク質
タンパク質名称 参考文献
環状ヌクレオチド代謝酵素 ホスホジエステラーゼ [2]
アデニル酸シクラーゼ [23][24][25]
膜タンパク質 細胞膜カルシウムATPアーゼ (plasma membrane Ca2+-ATPase; PMCA) [26][27][28]
NMDA型グルタミン酸受容体 [29]
代謝活性型グルタミン酸受容体 [30][31]
L型カルシウムチャネル [32][33]
P/Q型カルシウムチャネル [34]
IP3受容体 [35]
リン酸化酵素 ミオシン軽鎖キナーゼ (MLCK) [36][37][38][39]
Ca2+/カルモジュリン依存性タンパク質キナーゼI (CaMKI) [40]
Ca2+/カルモジュリン依存性タンパク質キナーゼII (CaMKII) [41][42]
Ca2+/カルモジュリン依存性タンパク質キナーゼIV (CaMKIV) [43]
Ca2+/カルモジュリン依存性タンパク質キナーゼキナーゼ (CaMKK) [44][45]
ホスホリラーゼキナーゼ [46]
脱リン酸化酵素 カルシニューリン [47][48]
細胞骨格系タンパク質 MAP2 [49]
タウ [49]
アデューシン [50]
ミオシン [51][52][53][54]
一酸化窒素合成酵素 [55][56]
熱ショックタンパク質70/90 [57][58]

 こうした様々なタンパク質と結合し、その活性や機能を制御することがカルモジュリンの機能であり、脳や神経細胞においては、神経突起形成[59][60]、軸索伸展[61][62][63]、シナプスの形成[64]、シナプス可塑性[65][66][67][68][69][70]とその誘導に関わる細胞内シグナルの伝達[71][72][73][74][75]、記憶・学習[76][77][78][79][80]をはじめ、様々な機能の中心的役割を果たす。また、リン酸化[81]糖化[82]メチル化[11]など翻訳後修飾を受け、機能を調節することが知られている[83][84]

カルモジュリンは、そのターゲットとなるCaMKII、カルシニューリン、アデニル酸シクラーゼなどの下流のエフェクター酵素の制御を通してのシナプス可塑性や記憶・学習に対する機能が指摘されてきた。また、ターゲットは多数あるが、神経入力のパターンに応じて異なる酵素を活性化し、状況に応じて適切な神経細胞機能を発現していると考えられている。例えば、海馬CA1領域における長期増強はNMDA受容体の活性化によりCa2+が流入し、カルモジュリンと結合することで下流の酵素を活性化して引き起こされる。CaMKIIαのノックアウトマウスにおいては、海馬のシェーファー側枝からCA1錐体細胞への長期増強が減弱することが報告されており[85]、また海馬依存的な空間学習に異常がみられることが報告されている[86]。また、最近ではCa2+流入に伴うスパインの構造的可塑性の誘導に関わることや、この過程における種々の酵素の活性化が報告されている。また、同様にカルモジュリンによって活性化されるアデニル酸シクラーゼ1、8やカルシニューリンもシナプス可塑性や記憶・学習に関与することが遺伝子改変動物などの研究によって報告されている。

サブファミリー

 ヒトのCalmodulin1、Calmodulin2、Calmodulin3は同一のアミノ酸配列のタンパク質をコードしており、それぞれ染色体上の14q24-q31、2p21.1-p21.3、19q13.2-q13.3に位置する(表2)[87]

表2. ヒトカルモジュリン遺伝子
タンパク質名称 NCBI遺伝子情報 NCBI mRNA情報 (RefSeq) HUGO遺伝子命名法委員会 (HGNC) Allen mouse brain
Calmodulin1 801 NM_006888 CALM1 12098
Calmodulin2 805 NM_001743 CALM2 12099
Calmodulin3 808 NM_005184 CALM3 12100

 その他、酵母植物昆虫からヒトまで真核生物に発現しており、特に脊椎動物の中では高い保存性を示す。

阻害剤

 1974年にWeissらが、カルモジュリンにより活性化される脳のホスホジエステラーゼに対するフェノチアジン誘導体の阻害効果の作用機序およびキネティクスを報告し、カルモジュリン阻害剤であることを示した[88](これに先立つ1968年、Hondaらはフェノチアジン誘導体の環状ヌクレオチドホスホジエステラーゼに対する阻害効果が脳由来の酵素と心臓由来の酵素で異なることを報告している[89])。この後、W-7[90]カルミダゾリウム[91]など、さまざまな物質がカルモジュリン阻害剤として働くことが見出されている[92][93]

疾患と関連するカルモジュリンの変異

 カルモジュリンの点突然変異が、カテコールアミン誘発性多形性心室性頻拍QT延長症候群、特発性心室細動で見出されている(表3)。

表3. 疾患と関連するカルモジュリンの変異
疾患名 遺伝子名 変異 文献
カテコールアミン誘発性多形性心室性頻拍 (CPVT) CALM1 N53I [94]
N97S [94]
QT延長症候群 (LQTS) CALM1 D129G [95]
F141L [95]
CALM2 D95V [96]
N97S [96]
N97I [95]
D133H [96]
CLAM3 D129G [97]
CPVT・LQTSの合併 CALM2 D131E [96]
Q135P [96]
特発性心室細動(IVF) CALM1 F89L [98]

 また、癌ゲノム解析により、多数の体細胞変異が見つかっているが、その機能については良く分かっていない[99][100][101]

カルモジュリンを用いたCa2+インディケーター

 カルモジュリンがCa2+依存的にターゲットペプチドと相互作用することを用いて、様々なGenetically-encoded Ca2+ indicatorが開発されている。大まかには、2色の異なる色の蛍光タンパク質間の蛍光共鳴エネルギー移動を用いてその2色の蛍光強度の比をレシオメトリック測定することが可能なFRETセンサー(Cameleonなど)と[102][103]円順列変異GFPを用いてその蛍光強度からCa2+濃度を測定する緑色蛍光プローブ(G-CaMPなど)がある[104][105]

 2000年代以降、これらの改良が進んでおり、変化率を大きくしたものや単一活動電位を記録できる高感度のもの、キネティクスが速いもの、さまざまな色のインディケーターなどが開発され、生きた動物個体の中での神経細胞やシナプスの活動を長期間観察するのに用いられている[106][107][108][109][110][111][112][113][114][115]

関連項目

参考文献

  1. Babu, Y.S., Bugg, C.E., & Cook, W.J. (1988).
    Structure of calmodulin refined at 2.2 A resolution. Journal of molecular biology, 204(1), 191-204. [PubMed:3145979] [WorldCat] [DOI]
  2. 2.0 2.1 S Kakiuchi, R Yamazaki
    Stimulation of the activity of cyclic 3',5'-nucleotide phosphodiesterase by calcium ion.
    Proc. Japan Acad. 46, 387-392:1970
  3. S Kakiuchi, R Yamazaki, H Nakajima
    Properties of a heat-stable phosphodiesterase activating factor isolated from brain extract
    Proc. Japan Acad. 46, 587-592:1970
  4. Kakiuchi, S., & Yamazaki, R. (1970).
    Calcium dependent phosphodiesterase activity and its activating factor (PAF) from brain studies on cyclic 3',5'-nucleotide phosphodiesterase (3). Biochemical and biophysical research communications, 41(5), 1104-10. [PubMed:4320714] [WorldCat] [DOI]
  5. Cheung, W.Y. (1970).
    Cyclic 3',5'-nucleotide phosphodiesterase. Demonstration of an activator. Biochemical and biophysical research communications, 38(3), 533-8. [PubMed:4315350] [WorldCat] [DOI]
  6. Teo, T.S., Wang, T.H., & Wang, J.H. (1973).
    Purification and properties of the protein activator of bovine heart cyclic adenosine 3',5'-monophosphate phosphodiesterase. The Journal of biological chemistry, 248(2), 588-95. [PubMed:4346337] [WorldCat]
  7. Teo, T.S., & Wang, J.H. (1973).
    Mechanism of activation of a cyclic adenosine 3':5'-monophosphate phosphodiesterase from bovine heart by calcium ions. Identification of the protein activator as a Ca2+ binding protein. The Journal of biological chemistry, 248(17), 5950-5. [PubMed:4353626] [WorldCat]
  8. 日高弘義、垣内史朗 編
    カルモデュリン―Ca2+受容蛋白質
    1981
  9. Stevens, F.C., Walsh, M., Ho, H.C., Teo, T.S., & Wang, J.H. (1976).
    Comparison of calcium-binding proteins. Bovine heart and brain protein activators of cyclic nucleotide phosphodiesterase and rabbit skeletal muscle troponin C. The Journal of biological chemistry, 251(15), 4495-500. [PubMed:181374] [WorldCat]
  10. Watterson, D.M., Harrelson, W.G., Keller, P.M., Sharief, F., & Vanaman, T.C. (1976).
    Structural similarities between the Ca2+-dependent regulatory proteins of 3':5'-cyclic nucleotide phosphodiesterase and actomyosin ATPase. The Journal of biological chemistry, 251(15), 4501-13. [PubMed:181375] [WorldCat]
  11. 11.0 11.1 Watterson, D.M., Sharief, F., & Vanaman, T.C. (1980).
    The complete amino acid sequence of the Ca2+-dependent modulator protein (calmodulin) of bovine brain. The Journal of biological chemistry, 255(3), 962-75. [PubMed:7356670] [WorldCat]
  12. Klee, C.B. (1977).
    Conformational transition accompanying the binding of Ca2+ to the protein activator of 3',5'-cyclic adenosine monophosphate phosphodiesterase. Biochemistry, 16(5), 1017-24. [PubMed:14663] [WorldCat] [DOI]
  13. Wolff, D.J., Poirier, P.G., Brostrom, C.O., & Brostrom, M.A. (1977).
    Divalent cation binding properties of bovine brain Ca2+-dependent regulator protein. The Journal of biological chemistry, 252(12), 4108-17. [PubMed:193856] [WorldCat]
  14. Dedman, J.R., Potter, J.D., Jackson, R.L., Johnson, J.D., & Means, A.R. (1977).
    Physicochemical properties of rat testis Ca2+-dependent regulator protein of cyclic nucleotide phosphodiesterase. Relationship of Ca2+-binding, conformational changes, and phosphodiesterase activity. The Journal of biological chemistry, 252(23), 8415-22. [PubMed:200611] [WorldCat]
  15. WY Cheung ed.
    Calcium and Cell Function: Volume 1 Calmodulin
    1980 Academic Press, New York, ISBN 1483204030
  16. Cheung, W.Y., Lynch, T.J., & Wallace, R.W. (1978).
    An endogenous Ca2+-dependent activator protein of brain adenylate cyclase and cyclic neucleotide phosphodiesterase. Advances in cyclic nucleotide research, 9, 233-51. [PubMed:208377] [WorldCat]
  17. 17.0 17.1 Babu, Y.S., Sack, J.S., Greenhough, T.J., Bugg, C.E., Means, A.R., & Cook, W.J. (1985).
    Three-dimensional structure of calmodulin. Nature, 315(6014), 37-40. [PubMed:3990807] [WorldCat] [DOI]
  18. Xia, Z., & Storm, D.R. (2005).
    The role of calmodulin as a signal integrator for synaptic plasticity. Nature reviews. Neuroscience, 6(4), 267-76. [PubMed:15803158] [WorldCat] [DOI]
  19. Linse, S., Helmersson, A., & Forsén, S. (1991).
    Calcium binding to calmodulin and its globular domains. The Journal of biological chemistry, 266(13), 8050-4. [PubMed:1902469] [WorldCat]
  20. Rhoads, A.R., & Friedberg, F. (1997).
    Sequence motifs for calmodulin recognition. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 11(5), 331-40. [PubMed:9141499] [WorldCat] [DOI]
  21. Tidow, H., & Nissen, P. (2013).
    Structural diversity of calmodulin binding to its target sites. The FEBS journal, 280(21), 5551-65. [PubMed:23601118] [WorldCat] [DOI]
  22. Marshall, C.B., Nishikawa, T., Osawa, M., Stathopulos, P.B., & Ikura, M. (2015).
    Calmodulin and STIM proteins: Two major calcium sensors in the cytoplasm and endoplasmic reticulum. Biochemical and biophysical research communications, 460(1), 5-21. [PubMed:25998729] [WorldCat] [DOI]
  23. Westcott, K.R., La Porte, D.C., & Storm, D.R. (1979).
    Resolution of adenylate cyclase sensitive and insensitive to Ca2+ and calcium-dependent regulatory protein (CDR) by CDR-sepharose affinity chromatography. Proceedings of the National Academy of Sciences of the United States of America, 76(1), 204-8. [PubMed:284333] [PMC] [WorldCat] [DOI]
  24. Krupinski, J., Coussen, F., Bakalyar, H.A., Tang, W.J., Feinstein, P.G., Orth, K., ..., & Gilman, A.G. (1989).
    Adenylyl cyclase amino acid sequence: possible channel- or transporter-like structure. Science (New York, N.Y.), 244(4912), 1558-64. [PubMed:2472670] [WorldCat] [DOI]
  25. Feinstein, P.G., Schrader, K.A., Bakalyar, H.A., Tang, W.J., Krupinski, J., Gilman, A.G., & Reed, R.R. (1991).
    Molecular cloning and characterization of a Ca2+/calmodulin-insensitive adenylyl cyclase from rat brain. Proceedings of the National Academy of Sciences of the United States of America, 88(22), 10173-7. [PubMed:1719547] [PMC] [WorldCat] [DOI]
  26. Gopinath, R.M., & Vincenzi, F.F. (1977).
    Phosphodiesterase protein activator mimics red blood cell cytoplasmic activator of (Ca2+-Mg2+)ATPase. Biochemical and biophysical research communications, 77(4), 1203-9. [PubMed:197955] [WorldCat] [DOI]
  27. Jarrett, H.W., & Penniston, J.T. (1977).
    Partial purification of the Ca2+-Mg2+ ATPase activator from human erythrocytes: its similarity to the activator of 3':5' - cyclic nucleotide phosphodiesterase. Biochemical and biophysical research communications, 77(4), 1210-6. [PubMed:197956] [WorldCat] [DOI]
  28. Vorherr, T., James, P., Krebs, J., Enyedi, A., McCormick, D.J., Penniston, J.T., & Carafoli, E. (1990).
    Interaction of calmodulin with the calmodulin binding domain of the plasma membrane Ca2+ pump. Biochemistry, 29(2), 355-65. [PubMed:2154244] [WorldCat] [DOI]
  29. Ehlers, M.D., Zhang, S., Bernhadt, J.P., & Huganir, R.L. (1996).
    Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell, 84(5), 745-55. [PubMed:8625412] [WorldCat] [DOI]
  30. Minakami, R., Jinnai, N., & Sugiyama, H. (1997).
    Phosphorylation and calmodulin binding of the metabotropic glutamate receptor subtype 5 (mGluR5) are antagonistic in vitro. The Journal of biological chemistry, 272(32), 20291-8. [PubMed:9242710] [WorldCat] [DOI]
  31. Nakajima, Y., Yamamoto, T., Nakayama, T., & Nakanishi, S. (1999).
    A relationship between protein kinase C phosphorylation and calmodulin binding to the metabotropic glutamate receptor subtype 7. The Journal of biological chemistry, 274(39), 27573-7. [PubMed:10488094] [WorldCat] [DOI]
  32. Peterson, B.Z., DeMaria, C.D., Adelman, J.P., & Yue, D.T. (1999).
    Calmodulin is the Ca2+ sensor for Ca2+ -dependent inactivation of L-type calcium channels. Neuron, 22(3), 549-58. [PubMed:10197534] [WorldCat] [DOI]
  33. Zühlke, R.D., Pitt, G.S., Deisseroth, K., Tsien, R.W., & Reuter, H. (1999).
    Calmodulin supports both inactivation and facilitation of L-type calcium channels. Nature, 399(6732), 159-62. [PubMed:10335846] [WorldCat] [DOI]
  34. Lee, A., Wong, S.T., Gallagher, D., Li, B., Storm, D.R., Scheuer, T., & Catterall, W.A. (1999).
    Ca2+/calmodulin binds to and modulates P/Q-type calcium channels. Nature, 399(6732), 155-9. [PubMed:10335845] [WorldCat] [DOI]
  35. Maeda, N., Kawasaki, T., Nakade, S., Yokota, N., Taguchi, T., Kasai, M., & Mikoshiba, K. (1991).
    Structural and functional characterization of inositol 1,4,5-trisphosphate receptor channel from mouse cerebellum. The Journal of biological chemistry, 266(2), 1109-16. [PubMed:1845986] [WorldCat]
  36. Walsh, M.P., Dabrowska, R., Hinkins, S., & Hartshorne, D.J. (1982).
    Calcium-independent myosin light chain kinase of smooth muscle. Preparation by limited chymotryptic digestion of the calcium ion dependent enzyme, purification, and characterization. Biochemistry, 21(8), 1919-25. [PubMed:6896283] [WorldCat] [DOI]
  37. Blumenthal, D.K., Takio, K., Edelman, A.M., Charbonneau, H., Titani, K., Walsh, K.A., & Krebs, E.G. (1985).
    Identification of the calmodulin-binding domain of skeletal muscle myosin light chain kinase. Proceedings of the National Academy of Sciences of the United States of America, 82(10), 3187-91. [PubMed:3858814] [PMC] [WorldCat] [DOI]
  38. Lukas, T.J., Burgess, W.H., Prendergast, F.G., Lau, W., & Watterson, D.M. (1986).
    Calmodulin binding domains: characterization of a phosphorylation and calmodulin binding site from myosin light chain kinase. Biochemistry, 25(6), 1458-64. [PubMed:3754463] [WorldCat] [DOI]
  39. Foster, C., Van Fleet, M., & Marshak, A. (1986).
    Tryptic digestion of myosin light chain kinase produces an inactive fragment that is activated on continued digestion. Archives of biochemistry and biophysics, 251(2), 616-23. [PubMed:3800388] [WorldCat] [DOI]
  40. Kennedy, M.B., & Greengard, P. (1981).
    Two calcium/calmodulin-dependent protein kinases, which are highly concentrated in brain, phosphorylate protein I at distinct sites. Proceedings of the National Academy of Sciences of the United States of America, 78(2), 1293-7. [PubMed:6785753] [PMC] [WorldCat] [DOI]
  41. Schulman, H., & Greengard, P. (1978).
    Stimulation of brain membrane protein phosphorylation by calcium and an endogenous heat-stable protein. Nature, 271(5644), 478-9. [PubMed:628428] [WorldCat] [DOI]
  42. Yamauchi, T., & Fujisawa, H. (1980).
    Evidence for three distinct forms of calmodulin-dependent protein kinases from rat brain. FEBS letters, 116(2), 141-4. [PubMed:7409141] [WorldCat] [DOI]
  43. Ohmstede, C.A., Jensen, K.F., & Sahyoun, N.E. (1989).
    Ca2+/calmodulin-dependent protein kinase enriched in cerebellar granule cells. Identification of a novel neuronal calmodulin-dependent protein kinase. The Journal of biological chemistry, 264(10), 5866-75. [PubMed:2538431] [WorldCat]
  44. Tokumitsu, H., Brickey, D.A., Glod, J., Hidaka, H., Sikela, J., & Soderling, T.R. (1994).
    Activation mechanisms for Ca2+/calmodulin-dependent protein kinase IV. Identification of a brain CaM-kinase IV kinase. The Journal of biological chemistry, 269(46), 28640-7. [PubMed:7961813] [WorldCat]
  45. Haribabu, B., Hook, S.S., Selbert, M.A., Goldstein, E.G., Tomhave, E.D., Edelman, A.M., ..., & Means, A.R. (1995).
    Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase. The EMBO journal, 14(15), 3679-86. [PubMed:7641687] [PMC] [WorldCat]
  46. Cohen, P., Burchell, A., Foulkes, J.G., Cohen, P.T., Vanaman, T.C., & Nairn, C. (1978).
    Identification of the Ca2+-dependent modulator protein as the fourth subunit of rabbit skeletal muscle phosphorylase kinase. FEBS letters, 92(2), 287-93. [PubMed:212300] [WorldCat] [DOI]
  47. Wang, J.H., & Desai, R. (1977).
    Modulator binding protein. Bovine brain protein exhibiting the Ca2+-dependent association with the protein modulator of cyclic nucleotide phosphodiesterase. The Journal of biological chemistry, 252(12), 4175-84. [PubMed:193860] [WorldCat]
  48. Klee, C.B., & Krinks, M.H. (1978).
    Purification of cyclic 3',5'-nucleotide phosphodiesterase inhibitory protein by affinity chromatography on activator protein coupled to Sepharose. Biochemistry, 17(1), 120-6. [PubMed:201280] [WorldCat] [DOI]
  49. 49.0 49.1 Lee, Y.C., & Wolff, J. (1984).
    Calmodulin binds to both microtubule-associated protein 2 and tau proteins. The Journal of biological chemistry, 259(2), 1226-30. [PubMed:6420403] [WorldCat]
  50. Gardner, K., & Bennett, V. (1986).
    A new erythrocyte membrane-associated protein with calmodulin binding activity. Identification and purification. The Journal of biological chemistry, 261(3), 1339-48. [PubMed:3511042] [WorldCat]
  51. Matsudaira, P.T., & Burgess, D.R. (1979).
    Identification and organization of the components in the isolated microvillus cytoskeleton. The Journal of cell biology, 83(3), 667-73. [PubMed:574874] [PMC] [WorldCat] [DOI]
  52. Carboni, J.M., Conzelman, K.A., Adams, R.A., Kaiser, D.A., Pollard, T.D., & Mooseker, M.S. (1988).
    Structural and immunological characterization of the myosin-like 110-kD subunit of the intestinal microvillar 110K-calmodulin complex: evidence for discrete myosin head and calmodulin-binding domains. The Journal of cell biology, 107(5), 1749-57. [PubMed:2460467] [PMC] [WorldCat] [DOI]
  53. Garcia, A., Coudrier, E., Carboni, J., Anderson, J., Vandekerkhove, J., Mooseker, M., ..., & Arpin, M. (1989).
    Partial deduced sequence of the 110-kD-calmodulin complex of the avian intestinal microvillus shows that this mechanoenzyme is a member of the myosin I family. The Journal of cell biology, 109(6 Pt 1), 2895-903. [PubMed:2687288] [PMC] [WorldCat] [DOI]
  54. Mooseker, M.S., & Coleman, T.R. (1989).
    The 110-kD protein-calmodulin complex of the intestinal microvillus (brush border myosin I) is a mechanoenzyme. The Journal of cell biology, 108(6), 2395-400. [PubMed:2525564] [PMC] [WorldCat] [DOI]
  55. Bredt, D.S., & Snyder, S.H. (1990).
    Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proceedings of the National Academy of Sciences of the United States of America, 87(2), 682-5. [PubMed:1689048] [PMC] [WorldCat] [DOI]
  56. Förstermann, U., Gorsky, L.D., Pollock, J.S., Ishii, K., Schmidt, H.H., Heller, M., & Murad, F. (1990).
    Hormone-induced biosynthesis of endothelium-derived relaxing factor/nitric oxide-like material in N1E-115 neuroblastoma cells requires calcium and calmodulin. Molecular pharmacology, 38(1), 7-13. [PubMed:2370855] [WorldCat]
  57. Nishida, E., Koyasu, S., Sakai, H., & Yahara, I. (1986).
    Calmodulin-regulated binding of the 90-kDa heat shock protein to actin filaments. The Journal of biological chemistry, 261(34), 16033-6. [PubMed:3782106] [WorldCat]
  58. Stevenson, M.A., & Calderwood, S.K. (1990).
    Members of the 70-kilodalton heat shock protein family contain a highly conserved calmodulin-binding domain. Molecular and cellular biology, 10(3), 1234-8. [PubMed:2154682] [PMC] [WorldCat] [DOI]
  59. Fink, C.C., Bayer, K.U., Myers, J.W., Ferrell, J.E., Schulman, H., & Meyer, T. (2003).
    Selective regulation of neurite extension and synapse formation by the beta but not the alpha isoform of CaMKII. Neuron, 39(2), 283-97. [PubMed:12873385] [WorldCat] [DOI]
  60. Takemoto-Kimura, S., Ageta-Ishihara, N., Nonaka, M., Adachi-Morishima, A., Mano, T., Okamura, M., ..., & Bito, H. (2007).
    Regulation of dendritogenesis via a lipid-raft-associated Ca2+/calmodulin-dependent protein kinase CLICK-III/CaMKIgamma. Neuron, 54(5), 755-70. [PubMed:17553424] [WorldCat] [DOI]
  61. Wen, Z., Guirland, C., Ming, G.L., & Zheng, J.Q. (2004).
    A CaMKII/calcineurin switch controls the direction of Ca(2+)-dependent growth cone guidance. Neuron, 43(6), 835-46. [PubMed:15363394] [WorldCat] [DOI]
  62. Ageta-Ishihara, N., Takemoto-Kimura, S., Nonaka, M., Adachi-Morishima, A., Suzuki, K., Kamijo, S., ..., & Bito, H. (2009).
    Control of cortical axon elongation by a GABA-driven Ca2+/calmodulin-dependent protein kinase cascade. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29(43), 13720-9. [PubMed:19864584] [PMC] [WorldCat] [DOI]
  63. Tojima, T., Itofusa, R., & Kamiguchi, H. (2014).
    Steering neuronal growth cones by shifting the imbalance between exocytosis and endocytosis. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(21), 7165-78. [PubMed:24849351] [PMC] [WorldCat] [DOI]
  64. Saneyoshi, T., Wayman, G., Fortin, D., Davare, M., Hoshi, N., Nozaki, N., ..., & Soderling, T.R. (2008).
    Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex. Neuron, 57(1), 94-107. [PubMed:18184567] [PMC] [WorldCat] [DOI]
  65. Malinow, R., Madison, D.V., & Tsien, R.W. (1988).
    Persistent protein kinase activity underlying long-term potentiation. Nature, 335(6193), 820-4. [PubMed:2847049] [WorldCat] [DOI]
  66. Malenka, R.C., Kauer, J.A., Perkel, D.J., Mauk, M.D., Kelly, P.T., Nicoll, R.A., & Waxham, M.N. (1989).
    An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature, 340(6234), 554-7. [PubMed:2549423] [WorldCat] [DOI]
  67. Silva, A.J., Stevens, C.F., Tonegawa, S., & Wang, Y. (1992).
    Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science (New York, N.Y.), 257(5067), 201-6. [PubMed:1378648] [WorldCat] [DOI]
  68. Mulkey, R.M., Endo, S., Shenolikar, S., & Malenka, R.C. (1994).
    Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature, 369(6480), 486-8. [PubMed:7515479] [WorldCat] [DOI]
  69. Zhuo, M., Zhang, W., Son, H., Mansuy, I., Sobel, R.A., Seidman, J., & Kandel, E.R. (1999).
    A selective role of calcineurin aalpha in synaptic depotentiation in hippocampus. Proceedings of the National Academy of Sciences of the United States of America, 96(8), 4650-5. [PubMed:10200317] [PMC] [WorldCat] [DOI]
  70. Matsuzaki, M., Honkura, N., Ellis-Davies, G.C., & Kasai, H. (2004).
    Structural basis of long-term potentiation in single dendritic spines. Nature, 429(6993), 761-6. [PubMed:15190253] [PMC] [WorldCat] [DOI]
  71. Bito, H., Deisseroth, K., & Tsien, R.W. (1996).
    CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression. Cell, 87(7), 1203-14. [PubMed:8980227] [WorldCat] [DOI]
  72. Hayashi, Y., Shi, S.H., Esteban, J.A., Piccini, A., Poncer, J.C., & Malinow, R. (2000).
    Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science (New York, N.Y.), 287(5461), 2262-7. [PubMed:10731148] [WorldCat] [DOI]
  73. Lee, S.J., Escobedo-Lozoya, Y., Szatmari, E.M., & Yasuda, R. (2009).
    Activation of CaMKII in single dendritic spines during long-term potentiation. Nature, 458(7236), 299-304. [PubMed:19295602] [PMC] [WorldCat] [DOI]
  74. Fujii, H., Inoue, M., Okuno, H., Sano, Y., Takemoto-Kimura, S., Kitamura, K., ..., & Bito, H. (2013).
    Nonlinear decoding and asymmetric representation of neuronal input information by CaMKIIα and calcineurin. Cell reports, 3(4), 978-87. [PubMed:23602566] [WorldCat] [DOI]
  75. Nishiyama, J., & Yasuda, R. (2015).
    Biochemical Computation for Spine Structural Plasticity. Neuron, 87(1), 63-75. [PubMed:26139370] [PMC] [WorldCat] [DOI]
  76. Silva, A.J., Paylor, R., Wehner, J.M., & Tonegawa, S. (1992).
    Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science (New York, N.Y.), 257(5067), 206-11. [PubMed:1321493] [WorldCat] [DOI]
  77. Wong, S.T., Athos, J., Figueroa, X.A., Pineda, V.V., Schaefer, M.L., Chavkin, C.C., ..., & Storm, D.R. (1999).
    Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. Neuron, 23(4), 787-98. [PubMed:10482244] [WorldCat] [DOI]
  78. Giese, K.P., Fedorov, N.B., Filipkowski, R.K., & Silva, A.J. (1998).
    Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science (New York, N.Y.), 279(5352), 870-3. [PubMed:9452388] [WorldCat] [DOI]
  79. Zeng, H., Chattarji, S., Barbarosie, M., Rondi-Reig, L., Philpot, B.D., Miyakawa, T., ..., & Tonegawa, S. (2001).
    Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. Cell, 107(5), 617-29. [PubMed:11733061] [WorldCat] [DOI]
  80. Nonaka, M., Kim, R., Fukushima, H., Sasaki, K., Suzuki, K., Okamura, M., ..., & Bito, H. (2014).
    Region-specific activation of CRTC1-CREB signaling mediates long-term fear memory. Neuron, 84(1), 92-106. [PubMed:25277455] [WorldCat] [DOI]
  81. Plancke, Y.D., & Lazarides, E. (1983).
    Evidence for a phosphorylated form of calmodulin in chicken brain and muscle. Molecular and cellular biology, 3(8), 1412-20. [PubMed:6621532] [PMC] [WorldCat] [DOI]
  82. Kowluru, R.A., Heidorn, D.B., Edmondson, S.P., Bitensky, M.W., Kowluru, A., Downer, N.W., ..., & Trewhella, J. (1989).
    Glycation of calmodulin: chemistry and structural and functional consequences. Biochemistry, 28(5), 2220-8. [PubMed:2541779] [WorldCat] [DOI]
  83. Sacks, D.B., Davis, H.W., Williams, J.P., Sheehan, E.L., Garcia, J.G., & McDonald, J.M. (1992).
    Phosphorylation by casein kinase II alters the biological activity of calmodulin. The Biochemical journal, 283 ( Pt 1), 21-4. [PubMed:1314563] [PMC] [WorldCat] [DOI]
  84. Quadroni, M., L'Hostis, E.L., Corti, C., Myagkikh, I., Durussel, I., Cox, J., ..., & Carafoli, E. (1998).
    Phosphorylation of calmodulin alters its potency as an activator of target enzymes. Biochemistry, 37(18), 6523-32. [PubMed:9572870] [WorldCat] [DOI]
  85. Silva, A.J., Stevens, C.F., Tonegawa, S., & Wang, Y. (1992).
    Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science (New York, N.Y.), 257(5067), 201-6. [PubMed:1378648] [WorldCat] [DOI]
  86. Silva, A.J., Paylor, R., Wehner, J.M., & Tonegawa, S. (1992).
    Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science (New York, N.Y.), 257(5067), 206-11. [PubMed:1321493] [WorldCat] [DOI]
  87. Berchtold, M.W., Egli, R., Rhyner, J.A., Hameister, H., & Strehler, E.E. (1993).
    Localization of the human bona fide calmodulin genes CALM1, CALM2, and CALM3 to chromosomes 14q24-q31, 2p21.1-p21.3, and 19q13.2-q13.3. Genomics, 16(2), 461-5. [PubMed:8314583] [WorldCat] [DOI]
  88. B Weiss, R. Fertel, R Figlin, and P Uzunov
    Selective alteration of the activity of the multiple forms of adenosine 3', 5'-monophosphate phosphodiesterase of rat cerebrum
    Mol. Pharmacol. 10, 615-625:1974
  89. Honda, F., & Imamura, H. (1968).
    Inhibition of cyclic 3',5'-nucleotide phosphodiesterase by phenothiazine and reserpine derivatives. Biochimica et biophysica acta, 161(1), 267-9. [PubMed:4298921] [WorldCat] [DOI]
  90. Tanaka, T., & Hidaka, H. (1980).
    Hydrophobic regions function in calmodulin-enzyme(s) interactions. The Journal of biological chemistry, 255(23), 11078-80. [PubMed:6254958] [WorldCat]
  91. H Van Belle
    R 24 571: A potent inhibitor of calmodulin-activated enzymes.
    Cell Calcium 2, 483-494:1981
  92. Martínez-Luis, S., Pérez-Vásquez, A., & Mata, R. (2007).
    Natural products with calmodulin inhibitor properties. Phytochemistry, 68(14), 1882-903. [PubMed:17400264] [WorldCat] [DOI]
  93. Mata, R., Figueroa, M., González-Andrade, M., Rivera-Chávez, J.A., Madariaga-Mazón, A., & Del Valle, P. (2015).
    Calmodulin inhibitors from natural sources: an update. Journal of natural products, 78(3), 576-86. [PubMed:25536331] [WorldCat] [DOI]
  94. 94.0 94.1 Nyegaard, M., Overgaard, M.T., Søndergaard, M.T., Vranas, M., Behr, E.R., Hildebrandt, L.L., ..., & Børglum, A.D. (2012).
    Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. American journal of human genetics, 91(4), 703-12. [PubMed:23040497] [PMC] [WorldCat] [DOI]
  95. 95.0 95.1 95.2 Crotti, L., Johnson, C.N., Graf, E., De Ferrari, G.M., Cuneo, B.F., Ovadia, M., ..., & George, A.L. (2013).
    Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation, 127(9), 1009-17. [PubMed:23388215] [PMC] [WorldCat] [DOI]
  96. 96.0 96.1 96.2 96.3 96.4 Makita, N., Yagihara, N., Crotti, L., Johnson, C.N., Beckmann, B.M., Roh, M.S., ..., & George, A.L. (2014).
    Novel calmodulin mutations associated with congenital arrhythmia susceptibility. Circulation. Cardiovascular genetics, 7(4), 466-74. [PubMed:24917665] [PMC] [WorldCat] [DOI]
  97. Reed, G.J., Boczek, N.J., Etheridge, S.P., & Ackerman, M.J. (2015).
    CALM3 mutation associated with long QT syndrome. Heart rhythm, 12(2), 419-22. [PubMed:25460178] [PMC] [WorldCat] [DOI]
  98. Marsman, R.F., Barc, J., Beekman, L., Alders, M., Dooijes, D., van den Wijngaard, A., ..., & Bezzina, C.R. (2014).
    A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence. Journal of the American College of Cardiology, 63(3), 259-66. [PubMed:24076290] [WorldCat] [DOI]
  99. CALM1 COSMIC database
  100. CALM2 COSMIC database
  101. CALM3 COSMIC database
  102. Romoser, V.A., Hinkle, P.M., & Persechini, A. (1997).
    Detection in living cells of Ca2+-dependent changes in the fluorescence emission of an indicator composed of two green fluorescent protein variants linked by a calmodulin-binding sequence. A new class of fluorescent indicators. The Journal of biological chemistry, 272(20), 13270-4. [PubMed:9148946] [WorldCat] [DOI]
  103. Miyawaki, A., Llopis, J., Heim, R., McCaffery, J.M., Adams, J.A., Ikura, M., & Tsien, R.Y. (1997).
    Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin. Nature, 388(6645), 882-7. [PubMed:9278050] [WorldCat] [DOI]
  104. Nakai, J., Ohkura, M., & Imoto, K. (2001).
    A high signal-to-noise Ca(2+) probe composed of a single green fluorescent protein. Nature biotechnology, 19(2), 137-41. [PubMed:11175727] [WorldCat] [DOI]
  105. Nagai, T., Sawano, A., Park, E.S., & Miyawaki, A. (2001).
    Circularly permuted green fluorescent proteins engineered to sense Ca2+. Proceedings of the National Academy of Sciences of the United States of America, 98(6), 3197-202. [PubMed:11248055] [PMC] [WorldCat] [DOI]
  106. Nagai, T., Yamada, S., Tominaga, T., Ichikawa, M., & Miyawaki, A. (2004).
    Expanded dynamic range of fluorescent indicators for Ca(2+) by circularly permuted yellow fluorescent proteins. Proceedings of the National Academy of Sciences of the United States of America, 101(29), 10554-9. [PubMed:15247428] [PMC] [WorldCat] [DOI]
  107. Palmer, A.E., Giacomello, M., Kortemme, T., Hires, S.A., Lev-Ram, V., Baker, D., & Tsien, R.Y. (2006).
    Ca2+ indicators based on computationally redesigned calmodulin-peptide pairs. Chemistry & biology, 13(5), 521-30. [PubMed:16720273] [WorldCat] [DOI]
  108. Wallace, D.J., Meyer zum Alten Borgloh, S., Astori, S., Yang, Y., Bausen, M., Kügler, S., ..., & Hasan, M.T. (2008).
    Single-spike detection in vitro and in vivo with a genetic Ca2+ sensor. Nature methods, 5(9), 797-804. [PubMed:19160514] [WorldCat] [DOI]
  109. Mank, M., Santos, A.F., Direnberger, S., Mrsic-Flogel, T.D., Hofer, S.B., Stein, V., ..., & Griesbeck, O. (2008).
    A genetically encoded calcium indicator for chronic in vivo two-photon imaging. Nature methods, 5(9), 805-11. [PubMed:19160515] [WorldCat] [DOI]
  110. Tian, L., Hires, S.A., Mao, T., Huber, D., Chiappe, M.E., Chalasani, S.H., ..., & Looger, L.L. (2009).
    Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators. Nature methods, 6(12), 875-81. [PubMed:19898485] [PMC] [WorldCat] [DOI]
  111. Zhao, Y., Araki, S., Wu, J., Teramoto, T., Chang, Y.F., Nakano, M., ..., & Campbell, R.E. (2011).
    An expanded palette of genetically encoded Ca²⁺ indicators. Science (New York, N.Y.), 333(6051), 1888-91. [PubMed:21903779] [PMC] [WorldCat] [DOI]
  112. Chen, T.W., Wardill, T.J., Sun, Y., Pulver, S.R., Renninger, S.L., Baohan, A., ..., & Kim, D.S. (2013).
    Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature, 499(7458), 295-300. [PubMed:23868258] [PMC] [WorldCat] [DOI]
  113. Thestrup, T., Litzlbauer, J., Bartholomäus, I., Mues, M., Russo, L., Dana, H., ..., & Griesbeck, O. (2014).
    Optimized ratiometric calcium sensors for functional in vivo imaging of neurons and T lymphocytes. Nature methods, 11(2), 175-82. [PubMed:24390440] [WorldCat] [DOI]
  114. Inoue, M., Takeuchi, A., Horigane, S., Ohkura, M., Gengyo-Ando, K., Fujii, H., ..., & Bito, H. (2015).
    Rational design of a high-affinity, fast, red calcium indicator R-CaMP2. Nature methods, 12(1), 64-70. [PubMed:25419959] [WorldCat] [DOI]
  115. Fosque, B.F., Sun, Y., Dana, H., Yang, C.T., Ohyama, T., Tadross, M.R., ..., & Schreiter, E.R. (2015).
    Neural circuits. Labeling of active neural circuits in vivo with designed calcium integrators. Science (New York, N.Y.), 347(6223), 755-60. [PubMed:25678659] [WorldCat] [DOI]