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TRANSGENIC APPROACHES TO ELUCIDATE THE ROLE OF PHOSPHOLAMBAN IN BASAL CONTRACTILITY AND DURING BETA-ADRENERGIC STIMULATION OF THE HEART

Brittsan, Angela Gail
http://rave.ohiolink.edu/etdc/view?acc_num=ucin960908353

Abstract Details

2000, PhD, University of Cincinnati, Medicine : Molecular, Cellular and Biochemical Pharmacology.
Phospholamban is a phosphoprotein in the cardiac sarcoplasmic reticulum (SR), which regulates the apparent affinity of the SR Ca2+-ATPase (SERCA2) for Ca2+. Phospholamban, in its dephosphorylated form, inhibits SERCA2 activity, and phosphorylation removes this inhibition. Transgenic approaches were utilized in this dissertation to further elucidate the role of phospholamban's regulation of SERCA2, in vivo, under normal and pathophysiological conditions, both in the presence and absence of b-agonist stimulation. 1) Phospholamban ablation has been shown to be associated with an attenuated response to b-agonist stimulation. However, it is not known if the b-adrenergic response of phospholamban-deficient hearts would be affected under altered thyroid conditions. Hypo- and hyperthyroidism were induced in phospholamban-deficient and wild-type mice, and their responses to isoproterenol stimulation were examined in work-performing hearts. A close linear correlation was observed between the magnitude of the contractile parameter response and the PLB/SERCA2 ratio in hypo-, eu- and hyperthyroid wild-type hearts. However, no response to b-agonist stimulation was observed in phospholamban-deficient hearts with altered thyroid conditions, indicating that the changes in the thyroid states of these hearts do not influence the effects of isoproterenol on cardiac function. 2) The PLB/SERCA2 stoichiometric ratio under saturating conditions is not known. 1.8-fold, 2.6-fold, 3.7-fold and 4.7-fold overexpression of a non-phosphorylatable form of phospholamban, relative to SERCA2, resulted in maximal inhibition of SERCA2's apparent affinity for Ca2+ at phospholamban expression levels of 2.6-fold or higher, indicating that saturation of the PLB/SERCA2 ratio occurs at 2.6:1, in vivo. 3) The contribution of phospholamban versus the other key cardiac phosphoproteins during b-adrenergic stimulation is not known. To determine phospholamban's contribution indirectly, a non-phosphorylatable form of phospholamban was inserted into hearts of phospholamban-deficient mice. Contrary to our predictions, the response of phospholamban mutant hearts to isoproterenol was not depressed, and these hearts developed compensatory mechanisms, which enabled them to be hypercontractile under basal conditions and fully respond to b-agonist stimulation. These findings indicate that when phospholamban is not capable of being phosphorylated on a beat-to-beat basis, compensatory mechanisms develop to accommodate the chronic inhibitory effects of the mutant form of phospholamban on SERCA2.
Evangelia Kranias (Advisor)
252 p.
Cardiac Muscle; Sarcoplasmic Reticulum; Phospholamban; Transgenic Mice; Mutagenesis

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Citations

  • Brittsan, A. G. (2000). TRANSGENIC APPROACHES TO ELUCIDATE THE ROLE OF PHOSPHOLAMBAN IN BASAL CONTRACTILITY AND DURING BETA-ADRENERGIC STIMULATION OF THE HEART [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin960908353

    APA Style (7th edition)

  • Brittsan, Angela. TRANSGENIC APPROACHES TO ELUCIDATE THE ROLE OF PHOSPHOLAMBAN IN BASAL CONTRACTILITY AND DURING BETA-ADRENERGIC STIMULATION OF THE HEART. 2000. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin960908353.

    MLA Style (8th edition)

  • Brittsan, Angela. "TRANSGENIC APPROACHES TO ELUCIDATE THE ROLE OF PHOSPHOLAMBAN IN BASAL CONTRACTILITY AND DURING BETA-ADRENERGIC STIMULATION OF THE HEART." Doctoral dissertation, University of Cincinnati, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=ucin960908353

    Chicago Manual of Style (17th edition)

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