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==阻害剤==
==阻害剤==
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、これがカルモジュリン阻害剤研究の先駆的な研究となった<ref><pubmed>4298921</pubmed></ref>。その後、!974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ている<ref>'''B Weiss, R. Fertel, R Figlin, and P Uzunov'''<br>Selective Alteration of the Activity of the Multiple Forms of Adenosine 3', 5'-Monophosphate Phosphodiesterase of Rat Cerebrum<br>''Mol. Pharmacol. 10, 615-625'':1981</ref>。この後、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<ref><pubmed>17400264 </pubmed></ref><ref><pubmed>25536331 </pubmed></ref>。
W-7<ref><pubmed>6254958 </pubmed></ref> ナフタレンスルホンアミド誘導体。カルモジュリンの疎水性領域に結合する。
W-7<ref><pubmed>6254958 </pubmed></ref> ナフタレンスルホンアミド誘導体。カルモジュリンの疎水性領域に結合する。
カルミダゾリウム<ref>'''H Van Belle'''<br>R 24 571: A potent inhibitor of calmodulin-activated enzymes.<br>''Cell Calcium 2, 483-494'':1981</ref>
カルミダゾリウム<ref>'''H Van Belle'''<br>R 24 571: A potent inhibitor of calmodulin-activated enzymes.<br>''Cell Calcium 2, 483-494'':1981</ref>


2015年7月24日 (金) 21:05時点における版

カルモジュリン　英：Calmodulin

要約

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、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、神経発生、軸策突起進展、長期記憶など様々な機能に関わる。

発見

1970年、Kakiuchiらは、ラット脳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[1]、このCa2+依存性を担う調節因子を見出した[2][3]。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[4]。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[5]、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[6][7]。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[8] [9]、アミノ酸配列が決定され[10]、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[11] [12] [13]。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[14][15]。

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[16]。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オングストロームであり、分子全体としては長軸が約65オングストロームの長さである[17]。

機能

カルモジュリンは脳内で10～100マイクロモル/リットルの濃度で発現しており[18]、細胞内で上昇したCa2+と結合し、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。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（MLCK、カルシニューリン、CaMKIV、NOS）、1-10モチーフ（CaMKII、シナプシン、ヒートショックプロテイン）、1-16モチーフ（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。


カルモジュリン結合タンパク質としては、環状ヌクレオチド代謝酵素（フォスフォジエステラーゼ[23][24]、アデニル酸シクラーゼ[25][26][27]）、膜タンパク質（Plasma membrane Ca2+-ATPase(PMCA)[28][29][30]、NMDA型グルタミン酸受容体[31]、代謝型グルタミン酸受容体[32][33]、L型カルシウムチャネル[34][35]、P/Q型カルシウムチャネル[36]、IP3 受容体[37]）、リン酸化酵素（ミオシン軽鎖キナーゼ(MLCK)[38][39][40][41]、Ca2+/CaM依存的キナーゼI[42]/II[43][44]/IV[45]、CaMキナーゼキナーゼ[46][47]、ホスホリラーゼキナーゼ[48]）、 脱リン酸化酵素（カルシニューリン）[49][50]、 細胞骨格系タンパク質（MAP2[51]、タウ[52]、アデューシン[53]、ミオシン）、一酸化窒素合成酵素[54][55]などが知られている。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る。

サブファミリー

Calmodulin1 Gene, RefSeq, HGNC, Allen mouse brain

Calmodulin2 Gene, RefSeq, HGNC, Allen mouse brain

Calmodulin3 Gene, RefSeq, HGNC, Allen mouse brain

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[56]。

阻害剤

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、これがカルモジュリン阻害剤研究の先駆的な研究となった[57]。その後、!974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ている[58]。この後、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[59][60]。 W-7[61] ナフタレンスルホンアミド誘導体。カルモジュリンの疎水性領域に結合する。 カルミダゾリウム[62]

疾患と関連するカルモジュリンの変異

カテコールアミン誘発性多形性心室性頻拍(CPVT)：CALM1（N53I[63], N97S[64]） QT延長症候群(LQTS)：CALM1(D129G[65], F141L[66]）CALM2(D95V[67], N97S[68], N97I[69], D133H[70]), CLAM3(D129G) [71] CPVT・LQTS： D131E[72], Q135P[73] [74] 特発性心室細動（IVF）：CALM1(F89L) [75]

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[76][77]、円順列変異GFPを用いてその蛍光強度からCa2+濃度を測定する単色蛍光プローブ（G-CaMPなど）がある[78][79]。2010年前後から、GCaMPの改良が進んでおり、さまざまな色のインディケーターの開発や脳活動を神経細胞レベルで長期間観察するのに用いられている[80][81][82][83]。


  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
  2. ↑ 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
  3. ↑ 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]
  4. ↑ 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]
  5. ↑ 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]
  6. ↑ 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]
  7. ↑ 日高弘義、垣内史朗　編
    カルモデュリン―Ca2+受容蛋白質
    :1981
  8. ↑ 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]
  9. ↑ 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]
  10. ↑ 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]
  11. ↑ 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]
  12. ↑ 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]
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    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]
  14. ↑ "WY Cheung, Calcium and Cell Function: Volume 1"
  15. ↑ 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]
  16. ↑ 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]
  17. ↑ 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]
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    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. ↑ S Kakiuchi, R Yamazaki
    Stimulation of the activity of cyclic 3',5'-nucleotide phosphodiesterase by calcium ion.
    Proc. Japan Acad. 46, 387-392:1970
  24. ↑ 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]
  25. ↑ 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]
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    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]
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    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]
  29. ↑ 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]
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    Interaction of calmodulin with the calmodulin binding domain of the plasma membrane Ca2+ pump. Biochemistry, 29(2), 355-65. [PubMed:2154244] [WorldCat] [DOI]
  31. ↑ 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]
  32. ↑ 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]
  33. ↑ 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]
  34. ↑ 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]
  35. ↑ 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]
  36. ↑ 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]
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    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]
  38. ↑ 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]
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    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]
  40. ↑ 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]
  41. ↑ 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]
  42. ↑ 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]
  43. ↑ 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]
  44. ↑ 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]
  45. ↑ 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]
  46. ↑ 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]
  47. ↑ 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]
  48. ↑ 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]
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