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Theses and Dissertations

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Browsing Theses and Dissertations by Subject "adhesion"

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    The voltage gated calcium channel β2 protein is required in the heart for control of cell proliferation and heart tube integrity
    (Colorado State University. Libraries, 2011) Chernyavskaya, Yelena, author; Garrity, Deborah Marie, advisor; Mykles, Donald, committee member; Miller, Charles, committee member; Reddy, A. S. N., committee member
    L-type calcium channels regulate calcium (LTCC) entry into cardiomyocytes. CACNB2 (β2) LTCC auxiliary subunits traffic the pore-forming CACNA subunit to the membrane and modulate channel kinetics. β2 is a Membrane Associated Guanylate Kinase (MAGUK) protein. A major role of MAGUK proteins is to scaffold cellular junctions and multi-protein complexes. To investigate developmental functions for β2.1, we depleted it in zebrafish using morpholinos. β2.1-depleted embryos developed cardiac edema and lethal cardiac defects. Ventricular cardiomyocytes proliferated at a slower rate, and failed to elongate their cell shape, which led to dysmorphic cardiac morphology and weakened contractility. Reduction in proliferation was marked by smaller heart fields and an increase in bmp4, an anti-proliferative marker. Thus, β2.1 helps regulate heart size by regulating the rate of mitosis and bmp4 expression in the ventricle. Additionally, cardiomyocytes depleted for β2.1 failed to accumulate N-cadherin at the membrane, and dissociated easily from neighboring myocytes under stress. Hence, we propose that β2 could function as a MAGUK scaffolding unit to maintain N-cadherin-based adherens junctions and heart tube integrity. To test this hypothesis we mutated the β2.1 residues necessary for interaction with the LTCC and observed its expression in cardiomyocytes using a GFP tag. Mutant β2.1 was still able to localize to the membrane supporting the possibility that it has a role in maintaining other protein complexes, such as adherens junctions.