L-type Ca2+ channels serve as a sensor of the SR Ca2+ for tuning the efficacy of Ca2+-induced Ca2+ release in rat ventricular myocytes

Takamatsu, Hajime

doi:10.1113/jphysiol.2003.050823

Cited by 33 publications

(16 citation statements)

References 22 publications

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“…The peak fluorescence ratio in these transients, i.e., peak fluorescence expressed relative to the resting level (F/Fo), was 2.72 ± 0.22 (N=5), and is comparable to previous measurements made using embryonic or embryonic stem cell derived myocytes (Korhonen et al, 2010; Lieu et al, 2009; Sauer et al, 2001). Calibrated intracellular free [Ca 2+ ] peaked at 320 ± 30 nM (N=5) which is also consistent with previous estimates from intact ventricular myocytes (Takamatsu et al, 2003) indicating the development of functional excitation-contraction coupling in these cells.…”

Section: Resultssupporting

confidence: 91%

Small Molecules Enable Cardiac Reprogramming of Mouse Fibroblasts with a Single Factor, Oct4

et al. 2014

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Summary It was recently shown that mouse fibroblasts could be reprogrammed into cells of a cardiac fate by forced expression of multiple transcription factors and microRNAs. To ultimately apply such reprogramming strategy for cell-based therapy or in vivo cardiac regeneration, reducing or eliminating the genetic manipulations by small molecules would be highly desirable. Here, we report the identification of a defined small-molecule cocktail that enables highly efficient conversion of mouse fibroblasts into cardiac cells with only one transcription factor, Oct4, without entering the pluripotent state. Small-molecule-induced cardiomyocytes spontaneously contract and exhibit a ventricular phenotype. Furthermore, such induced cardiomyocytes under our condition pass through a cardiac progenitor stage. This study lays the foundation for future pharmacological reprogramming approaches and provides a novel small-molecule condition to investigate the mechanisms underlying cardiac reprogramming process.

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Section: Resultssupporting

confidence: 91%

Small Molecules Enable Cardiac Reprogramming of Mouse Fibroblasts with a Single Factor, Oct4

et al. 2014

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“…In KO mice I Ca is reduced, possibly because the absence of NCX activity leads to an increase in subsarcolemmal Ca 2ϩ , which reduces I Ca through Ca 2ϩ -dependent inactivation (28). This reduction of I Ca would seem to be an explanation for the abbreviated KO AP (14,33). However, accelerated repolarization of the KO AP is evident even in the early phases of the AP (13,27).…”

Section: Discussionmentioning

confidence: 97%

Mechanism of shortened action potential duration in Na⁺-Ca²⁺ exchanger knockout mice

Pott¹,

Ren²,

Tran³

et al. 2007

American Journal of Physiology-Cell Physiology

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.-In cardiac-specific Na ϩ -Ca 2ϩ exchanger (NCX) knockout (KO) mice, the ventricular action potential (AP) is shortened. The shortening of the AP, as well as a decrease of the L-type Ca 2ϩ current (ICa), provides a critical mechanism for the maintenance of Ca 2ϩ homeostasis and contractility in the absence of NCX (Pott C, Philipson KD, Goldhaber JI. Excitation-contraction coupling in Na 1378 -1403, 2004) to determine the relative contributions of increased I to, reduced ICa, and reduced NCX current (I NCX ) on the shape and kinetics of the AP. Reduction of I Ca and elimination of INCX had relatively small effects on the duration of the AP in the computer model. In contrast, AP repolarization was substantially accelerated when I to was increased in the computer model. Thus, the increase in I to, and not the reduction of ICa or INCX, is likely to be the major mechanism of AP shortening in KO myocytes. We reported previously (27) that there are two fundamental mechanisms of adaptation to the absence of NCX: 1) a decrease in L-type Ca 2ϩ current (I Ca ) with an increased ECC gain and 2) a shortened and more rapidly repolarizing action potential (AP) that further reduces Ca 2ϩ influx. The more rapid repolarization of the AP renders it as effective as the wild-type (WT) AP in triggering sarcoplasmic reticular (SR) Ca 2ϩ release. These two mechanisms independently but synergistically limit Ca 2ϩ influx so that Ca 2ϩ homeostasis can be maintained by a low-capacity efflux mechanism (i.e., the plasma membrane Ca 2ϩ ATPase) while at the same time maintaining contractility.It is important to understand the mechanism responsible for the shortened AP in KO mice, since this mechanism plays a key role in assuring both Ca 2ϩ homeostasis and effective ECC in the absence of NCX. Both the elimination of NCX current (I NCX ) and the reduction of I Ca could potentially explain the abbreviated AP in KO myocytes. However, the dominant repolarizing current in cardiac ventricular myocytes is the transient outward current (I to ) (20). Recent studies (8,23,(35)(36)(37) have suggested that some of the cardiac K ϩ channel subunits that generate I to are tightly regulated by cytosolic Ca 2ϩ in their expression and activity, thus making regulation of the AP by I to in response to changes in Ca 2ϩ produced by knockout of NCX an attractive possibility.We report here that I to is increased in NCX KO mice and that the expression of the I to generating voltage-dependent K ϩ channel subunit Kv4.2 and the K ϩ channel interacting protein (KChIP) are upregulated. With the use of computer modeling, we further demonstrate that I to upregulation is the main determinant of AP shortening in KO mice. We hypothesize that altered Ca 2ϩ handling in NCX KO mice leads to upregulation of I to via an unknown mechanism. This in turn reduces AP duration and limits Ca 2ϩ influx. I to upregulation may comprise an important negative feedback mechanism against Ca 2ϩ overload in situations of reduced myocyte Ca 2ϩ extrusion capacity. METHODSGeneration of transgenic mi...

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“…The process of Ca 2+ -dependent inactivation requires the Ca 2+ binding protein, calmodulin, which binds to the intracellular C-terminus of α 1C to cause a conformational change that enables channel inactivation 37,38. In the heart, Ca 2+ influx through LTCCs opens ryanodine receptors in the sarcoplasmic reticulum to trigger Ca 2+ -induced Ca 2+ release and also mediates Ca 2+ -dependent inactivation of LTCCs to limit action potential duration 39. The process of Ca 2+ inactivation of LTCCs also may assume a physiological role in vascular SMCs, although there are only a few findings in this regard 40–42.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Ca ²⁺ Silences L-Type Ca ²⁺ Channels in Mesenteric Veins

Thakali

Kharade

Sonkusare

et al. 2010

Circulation Research

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L-type Ca2+ channels serve as a sensor of the SR Ca2+ for tuning the efficacy of Ca2+-induced Ca2+ release in rat ventricular myocytes

Cited by 33 publications

References 22 publications

Small Molecules Enable Cardiac Reprogramming of Mouse Fibroblasts with a Single Factor, Oct4

Small Molecules Enable Cardiac Reprogramming of Mouse Fibroblasts with a Single Factor, Oct4

Mechanism of shortened action potential duration in Na⁺-Ca²⁺ exchanger knockout mice

Intracellular Ca ²⁺ Silences L-Type Ca ²⁺ Channels in Mesenteric Veins

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L-type Ca2+ channels serve as a sensor of the SR Ca2+ for tuning the efficacy of Ca2+-induced Ca2+ release in rat ventricular myocytes

Cited by 33 publications

References 22 publications

Small Molecules Enable Cardiac Reprogramming of Mouse Fibroblasts with a Single Factor, Oct4

Small Molecules Enable Cardiac Reprogramming of Mouse Fibroblasts with a Single Factor, Oct4

Mechanism of shortened action potential duration in Na+-Ca2+ exchanger knockout mice

Intracellular Ca 2+ Silences L-Type Ca 2+ Channels in Mesenteric Veins

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Mechanism of shortened action potential duration in Na⁺-Ca²⁺ exchanger knockout mice

Intracellular Ca ²⁺ Silences L-Type Ca ²⁺ Channels in Mesenteric Veins