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Zhu T.,Washington University in St. Louis | Chappe J.C.,Washington University in St. Louis | Turk J.,Center for the Investigation of Membrane Excitability Diseases | Aurora R.,Washington University in St. Louis | And 10 more authors.
Journal of Biological Chemistry | Year: 2013

Background: PI(4,5)P2, mainly synthesized by PIP5KI, is essential for normal cell function. Results: Deficiency or overexpression of PIP5KI, which results in decrease or increase of PI(4,5)P2, respectively, impairs osteoclast differentiation and function. Conclusion: Optimal PIP5KI and PI(4,5)P2 expression are important for osteoclast function. Significance: This is the first demonstration that PIP5KI regulates cells in a bifunctional manner. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Toib A.,Center for the Investigation of Membrane Excitability Diseases | Zhang H.X.,Center for the Investigation of Membrane Excitability Diseases | Hyrc K.L.,Center for the Investigation of Membrane Excitability Diseases | Hyrc K.L.,Hope Center for Neurological Disorders | And 3 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2012

Transgenic mice overexpressing SUR1 and gain of function Kir6.2[{increment}N30, K185Q] KATP channel subunits, under cardiac α-myosin heavy chain (αMHC) promoter control, demonstrate arrhythmia susceptibility and premature death. Pregnant mice, crossed to carry double transgenic progeny, which harbor high levels of both overexpressed subunits, exhibit the most extreme phenotype and do not deliver any double transgenic pups. To explore the fetal lethality and embryonic phenotype that result from KATP overexpression, wild type (WT) and KATP overexpressing embryonic cardiomyocytes were isolated, cultured and voltage-clamped using whole cell and excised patch clamp techniques. Whole mount embryonic imaging, Hematoxylin and Eosin (H&E) and α smooth muscle actin (αSMA) immunostaining were used to assess anatomy, histology and cardiac development in KATP overexpressing and WT embryos. Double transgenic embryos developed in utero heart failure and 100% embryonic lethality by 11.5days post conception (dpc). KATP currents were detectable in both WT and KATP-overexpressing embryonic cardiomyocytes, starting at early stages of cardiac development (9.5dpc). In contrast to adult cardiomyocytes, WT and KATP-overexpressing embryonic cardiomyocytes exhibit basal and spontaneous KATP current, implying that these channels may be open and active under physiological conditions. At 9.5dpc, live double transgenic embryos demonstrated normal looping pattern, although all cardiac structures were collapsed, probably representing failed, non-contractile chambers. In conclusion, KATP channels are present and active in embryonic myocytes, and overexpression causes in utero heart failure and results in embryonic lethality. These results suggest that the KATP channel may have an important physiological role during early cardiac development. © 2012 Elsevier Ltd.

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