ダントロレンによるリアノジン受容体を分子標的とした新しい心不全・不整脈治療
悪性高熱症，カテコラミン誘発性多形性心室頻拍症（Catecholaminergic polymorphic ventricular tachycardia：CPVT）や心不全においては，リアノジン受容体（骨格筋型：RyR1，心筋型：RyR2）内のドメイン連関障害が，リアノジン受容体からのCa2+漏出の原因と考えられている．悪性高熱症の治療薬であるダントロレンは，RyR1に結合し，RyR1内のドメイン連関障害を是正することによってRyR1からのCa2+漏出を抑制する．同様に，イヌ心不全モデルやCPVT型knock-inマウスにおいてもダントンは，RyR2に結合し，RyR2からのCa2+漏出を抑制...
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| Published in | 山口医学 Vol. 62; no. 1; pp. 15 - 19 |
|---|---|
| Main Author | |
| Format | Journal Article |
| Language | Japanese |
| Published |
山口大学医学会
01.02.2013
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0513-1731 1880-4462 |
| DOI | 10.2342/ymj.62.15 |
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| Abstract | 悪性高熱症，カテコラミン誘発性多形性心室頻拍症（Catecholaminergic polymorphic ventricular tachycardia：CPVT）や心不全においては，リアノジン受容体（骨格筋型：RyR1，心筋型：RyR2）内のドメイン連関障害が，リアノジン受容体からのCa2+漏出の原因と考えられている．悪性高熱症の治療薬であるダントロレンは，RyR1に結合し，RyR1内のドメイン連関障害を是正することによってRyR1からのCa2+漏出を抑制する．同様に，イヌ心不全モデルやCPVT型knock-inマウスにおいてもダントンは，RyR2に結合し，RyR2からのCa2+漏出を抑制し，心不全の進展やCPVTを抑制する．このように，ダントロレンはRyR2を分子標的とした新しい心不全・不整脈治療薬となることが期待される． |
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| AbstractList | 「和文抄録」悪性高熱症, カテコラミン誘発性多形性心室頻拍症(Catecholaminergic polymorphic ventricular tachycardia: CPVT)や心不全においては, リアノジン受容体(骨格筋型: RyR1, 心筋型: RyR2)内のドメイン連関障害が, リアノジン受容体からのCa2+漏出の原因と考えられている. 悪性高熱症の治療薬であるダントロレンは, RyR1に結合し, RyR1内のドメイン連関障害を是正することによってRyR1からのCa2+漏出を抑制する. 同様に, イヌ心不全モデルやCPVT型knock-inマウスにおいてもダントンは, RyR2に結合し, RyR2からのCa2+漏出を抑制し, 心不全の進展やCPVTを抑制する. このように, ダントロレンはRyR2を分子標的とした新しい心不全・不整脈治療薬となることが期待される. 「はじめに」心不全は心筋の収縮, 弛緩の障害を基盤とする症候群であり, その原因として心筋細胞内Ca2+調節の異常が重要である. 悪性高熱症，カテコラミン誘発性多形性心室頻拍症（Catecholaminergic polymorphic ventricular tachycardia：CPVT）や心不全においては，リアノジン受容体（骨格筋型：RyR1，心筋型：RyR2）内のドメイン連関障害が，リアノジン受容体からのCa2+漏出の原因と考えられている．悪性高熱症の治療薬であるダントロレンは，RyR1に結合し，RyR1内のドメイン連関障害を是正することによってRyR1からのCa2+漏出を抑制する．同様に，イヌ心不全モデルやCPVT型knock-inマウスにおいてもダントンは，RyR2に結合し，RyR2からのCa2+漏出を抑制し，心不全の進展やCPVTを抑制する．このように，ダントロレンはRyR2を分子標的とした新しい心不全・不整脈治療薬となることが期待される． |
| Author | 小林, 茂樹 |
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| References | 4) Kobayashi S, Yamamoto T, Parness J, Ikemoto N. Antibody probe study of Ca2+ channel regulation by interdomain interaction within the ryanodine receptor. Biochem J 2004；380：561-569. 1) Yano M, Yamamoto T, Ikeda Y, Matsuzaki M. Mechanisms of Disease：ryanodine receptor defects in heart failure and fatal arrhythmia. Nat Clin Pract Cardiovasc Med 2006；3：43-52. 16) Kobayashi S, Yano M, Uchinoumi H, Suetomi T, Susa T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Yamamoto T, Matsuzaki M. Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2（R2474S/+）knock-in mouse model. Circ J 2010；74：2579-2584. 13) Kobayashi S, Yano M, Suetomi T, Ono M, Tateishi H, Mochizuki M, Xu X, Uchinoumi H, Okuda S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M. Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing inter-domain interactions within the ryanodine receptor. J Am Coll Cardiol 2009；53：1993-2005. 5) Oda T, Yano M, Yamamoto T, Tokuhisa T, Okuda S, Doi M, Ohkusa T, Ikeda Y, Kobayashi S, Ikemoto N, Matsuzaki M. Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure. Circulation 2005；111：3400-3410. 7) Yamamoto T, Yano M, Xu X, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Kobayashi S, Ikemoto N, Matsuzaki M. Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. Circulation 2008；117：762-772. 15) Xu X, Yano M, Uchinoumi H, Hino A, Suetomi T, Ono M, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Ikeda Y, Ikemoto N, Matsuzaki M. Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction. Biochem Biophys Res Commun 2010；394：660-666. 6) Mochizuki M, Yano M, Oda T, Tateishi H, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M. Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure. J Am Coll Cardiol 2007；49：1722-32. 12) Kobayashi S, Bannister ML, Gangopadhyay JP, Hamada T, Parness J, Ikemoto N. Dantrolene stabilizes domain interactions within the ryanodine receptor. J Biol Chem 2005；280：6580-6587. 3) Yamamoto T, El-Hayek R, Ikemoto N. Postulated role of interdomain interaction within the ryanodine receptor in Ca2+ channel regulation. J Biol Chem 2000；275：11618-11625. 14) Uchinoumi H, Yano M, Suetomi T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M. Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor. Circ Res 2010；106：1413-1424. 8) Tateishi H, Yano M, Mochizuki M, Suetomi T, Ono M, Xu X, Uchinoumi H, Okuda S, Oda T, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M. Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts. Cardiovasc Res 2009；81：536-45. 10) Liu Z, Wang R, Tian X, Zhong X, Gangopadhyay J, Cole R, Ikemoto N, Chen SR, Wagenknecht T. Dynamic, inter-subunit interactions between the N-terminal and central mutation regions of cardiac ryanodine receptor. J Cell Sci 2010 15；123：1775-1784. 17) McCauley MD, Wehrens XH. J. Targeting ryanodine receptors for anti-arrhythmic therapy. Acta Pharmacol Sin 2011；32：749-757. 9) Ono M, Yano M, Hino A, Suetomi T, Xu X, Susa T, Uchinoumi H, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M. Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca（2+） release in heart failure. Cardiovasc Res 2010；87（4）：609-617. 11) Paul-Pletzer K, Yamamoto T, Bhat MB, Ma J, Ikemoto N, Jimenez LS, Morimoto H, Williams PG, Ma J, Parness J. Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. J Biol Chem 2002；277：34918-34923. 2) Ikemoto N, Yamamoto T. Regulation of calcium release by interdomain interaction within ryanodine receptors. Front Biosci 2002；7：d671-683. |
| References_xml | – reference: 15) Xu X, Yano M, Uchinoumi H, Hino A, Suetomi T, Ono M, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Ikeda Y, Ikemoto N, Matsuzaki M. Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction. Biochem Biophys Res Commun 2010；394：660-666. – reference: 10) Liu Z, Wang R, Tian X, Zhong X, Gangopadhyay J, Cole R, Ikemoto N, Chen SR, Wagenknecht T. Dynamic, inter-subunit interactions between the N-terminal and central mutation regions of cardiac ryanodine receptor. J Cell Sci 2010 15；123：1775-1784. – reference: 1) Yano M, Yamamoto T, Ikeda Y, Matsuzaki M. Mechanisms of Disease：ryanodine receptor defects in heart failure and fatal arrhythmia. Nat Clin Pract Cardiovasc Med 2006；3：43-52. – reference: 9) Ono M, Yano M, Hino A, Suetomi T, Xu X, Susa T, Uchinoumi H, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M. Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca（2+） release in heart failure. Cardiovasc Res 2010；87（4）：609-617. – reference: 8) Tateishi H, Yano M, Mochizuki M, Suetomi T, Ono M, Xu X, Uchinoumi H, Okuda S, Oda T, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M. Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts. Cardiovasc Res 2009；81：536-45. – reference: 2) Ikemoto N, Yamamoto T. Regulation of calcium release by interdomain interaction within ryanodine receptors. Front Biosci 2002；7：d671-683. – reference: 13) Kobayashi S, Yano M, Suetomi T, Ono M, Tateishi H, Mochizuki M, Xu X, Uchinoumi H, Okuda S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M. Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing inter-domain interactions within the ryanodine receptor. J Am Coll Cardiol 2009；53：1993-2005. – reference: 14) Uchinoumi H, Yano M, Suetomi T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M. Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor. Circ Res 2010；106：1413-1424. – reference: 17) McCauley MD, Wehrens XH. J. Targeting ryanodine receptors for anti-arrhythmic therapy. Acta Pharmacol Sin 2011；32：749-757. – reference: 16) Kobayashi S, Yano M, Uchinoumi H, Suetomi T, Susa T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Yamamoto T, Matsuzaki M. Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2（R2474S/+）knock-in mouse model. Circ J 2010；74：2579-2584. – reference: 3) Yamamoto T, El-Hayek R, Ikemoto N. Postulated role of interdomain interaction within the ryanodine receptor in Ca2+ channel regulation. J Biol Chem 2000；275：11618-11625. – reference: 12) Kobayashi S, Bannister ML, Gangopadhyay JP, Hamada T, Parness J, Ikemoto N. Dantrolene stabilizes domain interactions within the ryanodine receptor. J Biol Chem 2005；280：6580-6587. – reference: 5) Oda T, Yano M, Yamamoto T, Tokuhisa T, Okuda S, Doi M, Ohkusa T, Ikeda Y, Kobayashi S, Ikemoto N, Matsuzaki M. Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure. Circulation 2005；111：3400-3410. – reference: 11) Paul-Pletzer K, Yamamoto T, Bhat MB, Ma J, Ikemoto N, Jimenez LS, Morimoto H, Williams PG, Ma J, Parness J. Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. J Biol Chem 2002；277：34918-34923. – reference: 6) Mochizuki M, Yano M, Oda T, Tateishi H, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M. Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure. J Am Coll Cardiol 2007；49：1722-32. – reference: 4) Kobayashi S, Yamamoto T, Parness J, Ikemoto N. Antibody probe study of Ca2+ channel regulation by interdomain interaction within the ryanodine receptor. Biochem J 2004；380：561-569. – reference: 7) Yamamoto T, Yano M, Xu X, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Kobayashi S, Ikemoto N, Matsuzaki M. Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. Circulation 2008；117：762-772. |
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| Snippet | 悪性高熱症，カテコラミン誘発性多形性心室頻拍症（Catecholaminergic polymorphic ventricular tachycardia：CPVT）や心不全においては，リアノジン受容体（骨格筋... 「和文抄録」悪性高熱症, カテコラミン誘発性多形性心室頻拍症(Catecholaminergic polymorphic ventricular tachycardia: CPVT)や心不全においては, リアノジン受容体(骨格... |
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| SubjectTerms | ダントロレン リアノジン受容体 心不全 心室頻拍 悪性高熱症 |
| Title | ダントロレンによるリアノジン受容体を分子標的とした新しい心不全・不整脈治療 |
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