: myamada@shinshu-u.ac.jp

Professor: Mitsuhiko Yamada
Assistant Professor: Tsutomu Nakada, Toshihide Kashihara

Research Projects

■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.

■Alteration in functions of LTCCs in heart failure

Heart failure is one of the leading courses of the death of adults in Japan. In heart failure, the heart cannot provide sufficient output to meet the circulatory demands of peripheral organs. 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. Recently, we for the first time found that in heart failure, the activity of LTCCs in t-tubules is dramatically decreased mainly due to the excessive dephosphorylation of the channels. We are now seeking for the signal transduction pathways regulating the dephosphorylation of t-tubular LTCCs. If the signal transduction pathways are identified, drugs modifying the pathway might be utilized in treatment of heart failure.

■Molecular mechanisms underlying the formation of couplons in cardiac t-tubules

In mammalian ventricle myocytes, clusters of LTCCs in t-tubules are closely apposed to clusters of ryanodine receptors (RyRs) (i.e. intracellular Ca²⁺ channels) in the sarcoplasmic reticulum. This complex of LTCCs and RyRs is referred to a couplon and plays a significant role in the effective cardiac CICR. We recently found that the structure of couplons is altered in heart failure. Thus, in order to find out drugs modulating the formation of couplons, we are trying to identify the molecules underlying the formation of couplons in cardiac myocytes.