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      Ca 2+ Microdomains Organized by Junctophilins

      a , b , c

      Cell calcium

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          Abstract

          Excitable cells typically possess junctional membrane complexes (JMCs) constructed by the plasma membrane and the endo/sarcoplasmic reticulum (ER/SR) for channel crosstalk. These JMCs are termed triads in skeletal muscle, dyads in cardiac muscle, peripheral couplings in smooth and developing striated muscles, and subsurface cisterns in neurons. Junctophilin subtypes contribute to the formation and maintenance of JMCs by serving as a physical bridge between the plasma membrane and ER/SR membrane in different cell types. In muscle cells, junctophilin deficiency prevents JMC formation and functional crosstalk between cell-surface Ca 2+ channels and ER/SR Ca 2+ release channels. Human genetic mutations in junctophilin subtypes are linked to congenital hypertrophic cardiomyopathy and neurodegenerative diseases. Furthermore, growing evidence suggests that dysregulation of junctophilins induces pathological alterations in skeletal and cardiac muscle.

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          Most cited references 86

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          Cardiac excitation-contraction coupling.

          Of the ions involved in the intricate workings of the heart, calcium is considered perhaps the most important. It is crucial to the very process that enables the chambers of the heart to contract and relax, a process called excitation-contraction coupling. It is important to understand in quantitative detail exactly how calcium is moved around the various organelles of the myocyte in order to bring about excitation-contraction coupling if we are to understand the basic physiology of heart function. Furthermore, spatial microdomains within the cell are important in localizing the molecular players that orchestrate cardiac function.
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            A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure.

            Diverse forms of injury and stress evoke a hypertrophic growth response in adult cardiac myocytes, which is characterized by an increase in cell size, enhanced protein synthesis, assembly of sarcomeres, and reactivation of fetal genes, often culminating in heart failure and sudden death. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs that were regulated during cardiac hypertrophy and heart failure. We describe >12 miRNAs that are up- or down-regulated in cardiac tissue from mice in response to transverse aortic constriction or expression of activated calcineurin, stimuli that induce pathological cardiac remodeling. Many of these miRNAs were similarly regulated in failing human hearts. Forced overexpression of stress-inducible miRNAs was sufficient to induce hypertrophy in cultured cardiomyocytes. Similarly, cardiac overexpression of miR-195, which was up-regulated during cardiac hypertrophy, resulted in pathological cardiac growth and heart failure in transgenic mice. These findings reveal an important role for specific miRNAs in the control of hypertrophic growth and chamber remodeling of the heart in response to pathological signaling and point to miRNAs as potential therapeutic targets in heart disease.
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              Junctophilins: a novel family of junctional membrane complex proteins.

               M Iino,  H Takeshima,  M Nishi (2000)
              Junctional complexes between the plasma membrane (PM) and endoplasmic/sarcoplasmic reticulum (ER/ SR) are a common feature of all excitable cell types and mediate cross-talk between cell surface and intracellular ion channels. We have identified the junctophilins (JPs), a novel conserved family of proteins that are components of the junctional complexes. JPs are composed of a carboxy-terminal hydrophobic segment spanning the ER/SR membrane and a remaining cytoplasmic domain that shows specific affinity for the PM. In mouse, there are at least three JP subtypes: JP-1, -2, and -3. JP-2 is abundantly expressed in the heart, and mutant mice lacking JP-2 exhibited embryonic lethality. Cardiac myocytes from the mutant mice showed deficiency of the junctional membrane complexes and abnormal Ca2+ transients. Our results suggest that JPs are important components of junctional membrane complexes.
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                Author and article information

                Journal
                8006226
                2840
                Cell Calcium
                Cell Calcium
                Cell calcium
                0143-4160
                1532-1991
                11 February 2015
                25 January 2015
                October 2015
                16 December 2016
                : 58
                : 4
                : 349-356
                Affiliations
                [a ]Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan, Tel: +81-75-753-4572, takeshim@ 123456pharm.kyoto-u.ac.jp
                [b ]Department of Medicine and Center for Research in Biological Systems, University of California San Diego, CA 92093, USA, Tel: +1-858-822-3422, mhoshijima@ 123456ucsd.edu
                [c ]Department of Internal Medicine, University of Iowa Carver College of Medicine, IA 52242, USA, Tel: +1-319-384-2890, long-sheng-song@ 123456uiowa.edu
                Author notes
                Corresponding author: Hiroshi Takeshima
                Article
                NIHMS662043
                10.1016/j.ceca.2015.01.007
                5159448
                25659516

                This manuscript version is made available under the CC BY-NC-ND 4.0 license.

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                Molecular biology

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