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Molecular Pharmacology (Pharmacology)

Staff List

Professor YAMADA Mitsuhiko
Senior Assistant Professor NAKADA Tsutomu
Assistant Professor KASHIHARA Toshihide


E-mail : myamada(at)
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Summary of Activity

Our research is mainly focused on the pathophysiology and pharmacology of cardiovascular ion channels and transporters at molecular, cellular and organ levels. Our goal is to delineate mechanisms underlying cardiovascular diseases and establish a novel concept for pharmacological treatment of the diseases. Specifically, the main target of our research is currently cardiac L-type Ca2+ channels (LTCCs). We are analyzing how LTCCs become arrhythmogenic in certain pathophysiological conditions, how the functions of LTCCs are modulated in heart failure and how the spatial arrangement of LTCCs in transverse (t)-tubules is organized at a molecular level.

Research Projects

■ Molecular mechanism underlying a positive inotropic effect of angiotensin II that is specific for immature cardiomyocytes
Angiotensin II (AngII) is crucial in cardiovascular regulation in perinatal mammalians. We recently found that AngII increases twitch Ca2+ transients of mouse immature but not mature cardiomyocytes by robustly activating CaV1.2 L-type Ca2+ channels through a novel signaling pathway involving angiotensin type 1 (AT1) receptors, β-arrestin2 and casein kinase 2. A β-arrestin-biased AT1 receptor agonist, TRV027, which activates β-arrestin and inhibits Gq/11 was as effective as AngII in activating L-type Ca2+ channels. Our results help understand the molecular mechanism by which AngII regulates the perinatal circulation and also suggest that β-arrestin-biased AT1 receptor agonists may be valuable therapeutics for pediatric heart failure.

■ Alteration in functions of LTCCs in heart failure
Heart failure is one of the leading courses of the death of adults in developed nations. There is a consensus that the essential pathophysiology of heart failure is the alteration in the Ca2+ handling in ventricular myocytes. In ventricular myocytes, a Ca2+ influx through LTCCs in t-tubules induces a large Ca2+ release from the sarcoplasmic reticulum (Ca2+-induced Ca2+ release (CICR)), thereby inducing the contraction of the myocytes. We for the first time found that in heart failure, the activity of LTCCs in t-tubules is dramatically decreased mainly due to excessive dephosphorylation of the channels. Furthermore, we recently found that Gi/o proteins activated by β2-adrenergic and M2-muscarinic receptors cause this abnormality by activating protein phosphatase 2A. Thus, we are seeking for considering a new strategy of heart failure therapy utilizing inhibitors of these receptors.

■ Regulation of cardiac action potentials by L-type Ca2+ channels and pharmacological treatment of long QT syndromes by L-type Ca2+ channel blockers
Cardiac LTCCs play an important role not only in the excitation-contraction coupling but in determination of the action potential duration of cardiac myocytes. We recently found that when the action potential duration is prolonged due to suppression of voltage-dependent K+ channels as is the case of some types of the long QT syndrome (a class of diseases causing fatal ventricular arrhythmias), the failure of LTCCs to deactivate at the end of the phase 2 repolarization leads to early afterdepolarizations. Based on this finding, we are seeking for a method to treat arrhythmias with LTCC blockers along with beta-adrenergic blockers.

■ Molecular mechanisms underlying junctional membrane-targeting of LTCCs
In cardiac and skeletal myocytes, L-type calcium channels (LTCC) form a functional signaling complex with ryanodine receptors at the junctional membrane (JM). Although the specific localization of LTCCs to JM is critical for excitation-contraction coupling, their targeting mechanism is unclear. Using dysgenic (α1S-null) GLT myotubes as model system, we recently found that proximal C-terminus of α1C is necessary for the JM-targeting of cardiac LTCCs. Efficiency of restoration of action potential-induced Ca2+ transient in GLT myotubes was significantly decreased by mutations in the targeting motif. Further studies on the JM-targeting of LTCCs would reveal molecular mechanisms underlying the excitation-contraction coupling of cardiac and skeletal myocytes.

Major Publications

1. Kashihara, T., Nakada, T., Kojima, K., Takeshita, T., and Yamada, M. (2017) Angiotensin II activates CaV1.2 Ca2+ channels through β-arrestin2 and casein kinase 2 in mouse immature cardiomyocytes. J. Physiol. (Lond.) 595: 4207–4225

2. Kashihara, T., Hirose, M., Shimojo, H., Nakada, T., Gomi, S., Hongo, M. and Yamada, M. (2014) β2-Adrenergic and M2-muscarinic receptors decrease basal t-tubular L-type Ca2+ channel activity and suppress ventricular contractility in heart failure. Eur. J. Pharmacol. 724:122-131

3. Nakada, T., Flucher, B.E., Kashihara, T., Sheng, X., Shibazaki, T., Horiuchi-Hirose, M., Gomi, S., Hirose, M., and Yamada, M. (2012) Proximal C-terminus of α1C subunits is necessary for junctional membrane-targeting of cardiac L-type calcium channels. Biochem. J. 448: 221-231

4. Sheng, X, Nakada, T., Kobayashi, M., Kashihara, T., Shibazaki, T., Horiuchi-Hirose, M., Gomi, S., Hirose, M., Aoyama, T., Yamada, M. (2012) Two mechanistically distinct effects of dihydropyridine nifedipine on CaV1.2 L-type Ca2+ channels revealed by Timothy syndrome mutation. Eur. J. Pharmacol. 685: 15-23

5. Kashihara, T., Nakada, T., Shimojo, H., Horiuchi-Hirose, M., Gomi, S., Shibazaki, T., Sheng, X., Hirose, M., Hongo, M., and Yamada, M. (2012) Chronic receptor-mediated activation of Gi/o proteins alters basal t-tubular and sarcolemmal L-type Ca2+ channel activity through phosphatases in heart failure. Am. J. Physiol. Heart Circ. Physiol. 302: H1645-H1654

6. Horiuchi-Hirose, M., Kashihara, T., Nakada, T., Kurebayashi, N., Shimojo, H., Shibazaki, T., Sheng, X., Yano, S., Hirose, M., Hongo, M., Sakurai, T., Moriizumi, T., Ueda, H., and Yamada, M. (2011) Decrease in the density of t-tubular L-type Ca2+ channel currents in failing ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 300(3): H978-88

7. Yamada, M. (2011) Acid-sensing ion channels in blood volume regulation. Circ. J. 75(4): 781-782

8. Yamada, M. (2010) Mitochondrial ATP-sensitive K+ channels, protectors of the heart. J. Physiol. (Lond.) 582: 283-286

9. Yamada, M., Ohta, K., Niwa, A., Tsujino, N., Nakada, T., and Hirose, M.(2008) Contribution of L-type Ca2+ channels to early afterdepolarizations induced by IKr and IKs channel suppression in guinea-pig ventricular myocytes. J. Membr. Biol. 222: 151-166

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