Phospholamban (PLB) is a protein which inhibits the SR Ca2+-ATPase. Phosphorylation of PLB relives this inhibition in vitro and there is substantial evidence that PLB modulates cardiac contractility in vivo. There is some evidence for a similar role for PLB in smooth muscle. Recently, Dr. Evangelia Kranias has produced a PLB """"""""knockout"""""""" (PLB-) mouse. The investigator proposes to use this mouse as a model to study the role of PLB in smooth muscle in vivo. Preliminary data are presented to support the hypothesis that PLB is an important modulator of intercellular Ca2+ and a significant determinant of smooth muscle contractility. This project has three specific aims. In the first aim, the investigator proposes to quantitate and compare contractility in smooth muscle from the PLB- mouse to that in age-matched wild type mice. The initial studies will focus on the tonic aorta and the phasic portal vein as representative vascular preparations and the longitudinal ileum and trachea preparations, representative of enteric and airway smooth muscle. These studies will also be extended to resistance arteries. The role of PLB in baseline contractile functions, as well as its importance in relaxation mediated by CAMP or CGMP pathways will be determined. In this Aim the investigator will also verify the presence of PLB in wild type muscles and establish the levels of this protein and of the Ca2+- ATPase.
The second Aim will test the hypothesis that alterations in contractility in PLB-smooth muscles are due to changes in Ca2+ handling attributable to altered SR function. These tests will include fluorescent measurements of (Ca2+)I and the use of specific inhibitors of SR Ca2+ release and Ca2+ uptake. A goal of this aim is to determine the magnitude and investigate the nature of potential mechanisms that may compensate for the absence of PLB.
The third aim i s to determine the effects of the absence of PLB on the Ca2+ pump rate in vivo, and to quantify the baseline level of PLB inhibition of the pump in normal tissue.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Physiology Study Section (PHY)
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University of Cincinnati
Schools of Medicine
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Oloizia, Brian; Paul, Richard J (2008) Ca2+ clearance and contractility in vascular smooth muscle: evidence from gene-altered murine models. J Mol Cell Cardiol 45:347-62
Gu, Min; Thorne, George D; Wardle, Robert L et al. (2005) Ca2+-independent hypoxic vasorelaxation in porcine coronary artery. J Physiol 562:839-46
Ishida, Yukisato; Paul, Richard J (2005) Ca2+ clearance in smooth muscle: lessons from gene-altered mice. J Smooth Muscle Res 41:235-45
Sutliff, Roy L; Conforti, Laura; Weber, Craig S et al. (2004) Regulation of the spontaneous contractile activity of the portal vein by the sarcoplasmic reticulum: evidence from the phospholamban gene-ablated mouse. Vascul Pharmacol 41:197-204
Nobe, Hiromi; Nobe, Koji; Fazal, Fabeha et al. (2003) Rho kinase mediates serum-induced contraction in fibroblast fibers independent of myosin LC20 phosphorylation. Am J Physiol Cell Physiol 284:C599-606
Paul, R J; Shull, G E; Kranias, E G (2002) The sarcoplasmic reticulum and smooth muscle function: evidence from transgenic mice. Novartis Found Symp 246:228-38; discussion 238-43, 272-
Thorne, George D; Conforti, Laura; Paul, Richard J (2002) Hypoxic vasorelaxation inhibition by organ culture correlates with loss of Kv channels but not Ca(2+) channels. Am J Physiol Heart Circ Physiol 283:H247-53
Nobe, K; Paul, R J (2001) Distinct pathways of Ca(2+) sensitization in porcine coronary artery: effects of Rho-related kinase and protein kinase C inhibition on force and intracellular Ca(2+). Circ Res 88:1283-90
Nobe, K; Sutliff, R L; Kranias, E G et al. (2001) Phospholamban regulation of bladder contractility: evidence from gene-altered mouse models. J Physiol 535:867-78
Fortner, C N; Breyer, R M; Paul, R J (2001) EP2 receptors mediate airway relaxation to substance P, ATP, and PGE2. Am J Physiol Lung Cell Mol Physiol 281:L469-74

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