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[beta]-Adrenergic receptor ([beta]AR) stimulation increases cytosolic Ca[sup.2+] to physiologically augment cardiac contraction, whereas excessive [beta]AR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca[sup.2+]-calmodulin-dependent protein kinase II (CaMKII) is a recently identified downstream element of the [beta]AR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in [beta]AR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive [beta]AR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and [beta]AR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to [beta]AR signaling., Author(s): Rong Zhang [1, 8]; Michelle S C Khoo [1, 8]; Yuejin Wu [1, 8]; Yingbo Yang [1, 8]; Chad E Grueter [2]; Gemin Ni [1]; Edward E Price, Jr. [...]

Author(s): Peter J. Mohler [1, 2]; Jean-Jacques Schott [2, 3]; Anthony O. Gramolini [1]; Keith W. Dilly [4]; Silvia Guatimosim [4]; William H. duBell [5]; Long-Sheng Song [4]; Karine Haurogné [...]

Research has been conducted on the common cause of sudden cardiac death, arrhythmias. The authors suggest that ryanodine receptor channels can trigger fatal cardial arrhythmias explaining catecholaminergic polymorphic venticular tachycardia.

Molecular identification of a TTX-sensitive [Ca.sup.2+] current. Am J Physiol Cell Physiol 280: C1327-C1339, 2001.--The TTX-sensitive [Ca.sup.2+] current [[I.sub.Ca(TTX)]] observed in cardiac myocytes under [Na.sup.+]-free conditions was investigated using patch-clamp and [Ca.sup.2+]-imaging methods. [Cs.sup.+] and [Ca.sup.2+] were found to contribute to [I.sub.Ca(TTX)], but [TEA.sup.+] and N-methyl-D-glucamine ([NMDG.sup.+]) did not. HEK-293 cells transfected with cardiac [Na.sup.+] channels exhibited a current that resembled [I.sub.Ca(TTX)] in cardiac myocytes with regard to voltage dependence, inactivation kinetics, and ion selectivity, suggesting that the cardiac [Na.sup.+] channel itself gives rise to [I.sub.Ca(TTX)]. Furthermore, repeated activation of [I.sub.Ca(TTX)] led to a 60% increase in intracellular [Ca.sup.2+] concentration, confirming [Ca.sup.2+] entry through this current. [Ba.sup.2+] permeation of [I.sub.Ca(TTX)], reported by others, did not occur in rat myocytes or in HEK-293 cells expressing cardiac [Na.sup.+] channels under our experimental conditions. The report of block of [I.sub.Ca(TTX)] in guinea pig heart by mibefradil (10 [micro]M) was supported in transfected HEK-293 cells, but [Na.sup.+] current was also blocked (half-block at 0.45 [micro]M). We conclude that [I.sub.Ca(TTX)] reflects current through cardiac [Na.sup.+] channels in [Na.sup.+]-free (or 'null') conditions. We suggest that the current be renamed [I.sub.Na(null)] to more accurately reflect the molecular identity of the channel and the conditions needed for its activation. The relationship between [I.sub.Na(null)] and [Ca.sup.2+] flux through slip-mode conductance of cardiac [Na.sup.+] channels is discussed in the context of ion channel biophysics and 'permeation plasticity.' tetrodotoxin; excitation-contraction coupling; sodium channel; calcium channel; ventricular myocyte

Esposito, Giovanni, L. F. Santana, Keith Dilly, Jader Dos Santos Cruz, Lan Mao, W. J. Lederer, and Howard A. Rockman. Cellular and functional defects in a mouse model of heart failure. Am J Physiol Heart Circ Physiol 279: H3101-H3112, 2000.--Heart failure and dilated cardiomyopathy develop in mice that lack the muscle LIM protein (MLP) gene ([MLP.sup.-/-]). The character and extent of the heart failure that occurs in [MLP.sup.-/-] mice were investigated using echocardiography and in vivo pressure-volume (P-V) loop measurements. P-V loop data were obtained with a new method for mice (sonomicrometry) using two pairs of orthogonal piezoelectric crystals implanted in the endocardial wall. Sonomicrometry revealed right-shifted P-V loops in [MLP.sup.-/-] mice, depressed systolic contractility, and additional evidence of heart failure. Cellular changes in [MLP.sup.-/-] mice were examined in isolated single cells using patch-clamp and confocal [Ca.sup.2+] concentration ([[Ca.sup.2+]]) imaging techniques. This cellular investigation revealed unchanged [Ca.sup.2+] currents and [Ca.sup.2+] spark characteristics but decreased intracellular [[Ca.sup.2+]] transients and contractile responses and a defect in excitation-contraction coupling. Normal cellular and whole heart function was restored in [MLP.sup.-/-] mice that express a cardiac-targeted transgene, which blocks the function of [Beta]-adrenergic receptor ([Beta]-AR) kinase-1 ([Beta]ARK1). These data suggest that, despite the persistent stimulus to develop heart failure in [MLP.sup.-/-] mice (i.e., loss of the structural protein MLP), downregulation and desensitization of the [Beta]-ARs may play a pivotal role in the pathogenesis. Furthermore, this work suggests that the inhibition of [Beta]ARK1 action may prove an effective therapy for heart failure. contractility; [Beta]-adrenergic receptor; excitation-contraction coupling; calcium signaling; transgenic; [Beta]-adrenergic receptor kinase

DuBell, W. H., W. J. Lederer, and T. B. Rogers. [K.sup.+] currents responsible for repolarization in mouse ventricle and their modulation by FK-506 and rapamycin. Am. J. Physiol. Heart Circ. Physiol. 278: H886-H897, 2000.--Modulation of mouse ventricular action potentials and [K.sup.+] currents was examined using the whole cell patch-clamp technique. The composite mouse ventricular [K.sup.+] current (consisted of an outward transient followed by a slowly decaying sustained component. Use of the [K.sup.+] channel blockers tetraethylammonium and 4-aminopyridine and a transgenic mouse model revealed three pharmacologically and kinetically distinct currents: [I.sub.to], which contributed to the transient component; [I.sub.K], which contributed to the sustained component; and a slowly activating current ([I.sub.slow]), which contributed to both components. The immunosuppressant FK-506 increased action potential duration at 90% repolarization by 66.7% by decreasing the sustained component (-48% at + 60 mV) and prolonging recovery from inactivation (by 26% at 200 ms) of the transient component. These effects were isolated to [I.sub.K] and [I.sub.to], respectively. Rapamycin had strikingly similar effects on these currents. Both FK-506 and rapamycin are known to target the immunophilin FKBP12. Thus we conclude that FKBP12 modulates specific mouse [K.sup.+] channels, and thus the mouse ventricular action potential, by interacting directly with [K.sup.+] channel proteins or with other associated regulatory proteins. transient outward current; FK-binding proteins; Kv1.5