摘要:

Abstract—Calcineurin, a calcium/calmodulin-regulated protein phosphatase, modulates gene expression in cardiac and skeletal muscles during development and in remodeling responses such as cardiac hypertrophy that are evoked by environmental stresses or disease. Recently, we identified two genes encoding proteins (MCIP1 and MCIP2) that are enriched in striated muscles and that interact with calcineurin to inhibit its enzymatic activity. In the present study, we show that expression of MCIP1 is regulated by calcineurin activity in hearts of mice with cardiac hypertrophy, as well as in cultured skeletal myotubes. In contrast, expression of MCIP2 in the heart is not altered by activated calcineurin but responds to thyroid hormone, which has no effect on MCIP1. A ≈900-bp intragenic segment located between exons 3 and 4 of the MCIP1 gene functions as an alternative promoter that responds to calcineurin. This region includes a dense cluster of 15 consensus binding sites for NF-AT transcription factors. Because MCIP proteins can inhibit calcineurin, these results suggest that MCIP1 participates in a negative feedback circuit to diminish potentially deleterious effects of unrestrained calcineurin activity in cardiac and skeletal myocytes. Inhibitory effects of MCIP2 on calcineurin activity may be pertinent to gene switching events driven by thyroid hormone in striated muscles. The full text of this article is available at http://www.circresaha.org.

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Abstract—The control of intracellular calcium is central to regulation of contractile force in cardiac muscle. This review illustrates how analysis of the control of calcium requires an integrated approach in which several systems are considered. Thus, the calcium content of the sarcoplasmic reticulum (SR) is a major determinant of the amount of Ca2+released from the SR and the amplitude of the Ca2+transient. The amplitude of the transient, in turn, controls Ca2+fluxes across the sarcolemma and thence SR content. This control of SR content influences the response to maneuvers that modify, for example, the properties of the SR Ca2+release channel or ryanodine receptor. Specifically, modulation of the open probability of the ryanodine receptor produces only transient effects on the Ca2+transient as a result of changes of SR content. These interactions between various Ca2+fluxes are modified by the Ca2+buffering properties of the cell. Finally, we predict that, under some conditions, the above interactions can result in instability (such as alternans) rather than ordered control of contractility.

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Abstract—Voltage-dependent L-type Ca2+channels are multisubunit transmembrane proteins, which allow the influx of Ca2+(ICa) essential for normal excitability and excitation-contraction coupling in cardiac myocytes. A variety of different receptors and signaling pathways provide dynamic regulation ofICain the intact heart. The present review focuses on recent evidence describing the molecular details of regulation of L-type Ca2+channels by protein kinase A (PKA) and protein kinase C (PKC) pathways. Multiple G protein–coupled receptors act through cAMP/PKA pathways to regulate L-type channels. &bgr;-Adrenergic receptor stimulation results in a marked increase inICa, which is mediated by a cAMP/PKA pathway. Growing evidence points to an important role of localized signaling complexes involved in the PKA-mediated regulation ofICa, including A-kinase anchor proteins and binding of phosphatase PP2a to the carboxyl terminus of the &agr;1C(Cav1.2) subunit. Both &agr;1Cand &bgr;2asubunits of the channel are substrates for PKA in vivo. The regulation of L-type Ca2+channels by Gq-linked receptors and associated PKC activation is complex, with both stimulation and inhibition ofICabeing observed. The amino terminus of the &agr;1Csubunit is critically involved in PKC regulation. Crosstalk between PKA and PKC pathways occurs in the modulation ofICa. Ultimately, precise regulation ofICais needed for normal cardiac function, and alterations in these regulatory pathways may prove important in heart disease.

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Abstract—Combined experimental and theoretical developments have demonstrated that in addition to preexisting electrophysiological heterogeneities, cardiac electrical restitution properties contribute to breakup of reentrant wavefronts during cardiac fibrillation. Developing therapies that favorably alter electrical restitution properties have promise as a new paradigm for preventing fibrillation.

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID