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Cardiovascular Research 2000 45(4):925-933; doi:10.1016/S0008-6363(99)00410-1
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Biphasic redistribution of muscarinic receptor and the altered receptor phosphorylation and gene transcription are underlying mechanisms in the rat heart during sepsis

Lin-Wang Donga, Chaoshu Tangb and Maw-Shung Liua,*

aDepartment of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104-1028, USA
bLaboratory of Shock Research, Beijing Medical University, Beijing, China

* Corresponding author. Tel.: +1-314-577-8244; fax: +1-314-577-8233

Objective: The purpose of this study was to investigate intracellular redistribution of muscarinic cholinergic receptor (m2AChR) and the roles of receptor phosphorylation and gene transcription as underlying mechanisms in the rat heart during different phases of sepsis. Methods: Sepsis was induced by cecal ligation and puncture (CLP). The density of m2AChR in the sarcolemmal and light vesicle fractions was studied using [3H]-quinuclidinyl benzilate ([3H]-QNB). Phosphorylation of m2AChR was studied by labeling of the myocardial ATP pool by perfusing isolated hearts with [32P]H3PO4 followed by identification of the phosphorylated m2AChR with SDS–PAGE. The steady-state level of m2AChR mRNA was determined by RT-PCR and Southern blot analysis. Results: Septic rat hearts exhibit an initial hypercardiodynamic (9 h after CLP, early sepsis) and a subsequent hypocardiodynamic (18 h after CLP, late sepsis) state. During early sepsis, the Bmax for [3H]-QNB binding was increased in sarcolemma (+69%) but decreased in light vesicles (–22%), whereas during late sepsis, the Bmax was decreased in sarcolemma (–20%) but increased in light vesicles (+32%). The sum of Bmax for sarcolemmal and light vesicle fractions was increased during early sepsis (+43%) but decreased during late sepsis (–14%). The phosphorylation of m2AChR was decreased during early sepsis (–73%) but increased during late sepsis (+36% to +90%). The m2AChR mRNA abundance was increased during early sepsis (+52%) but decreased during late sepsis (–28%). Conclusions: The m2AChR in the rat heart was externalized from light vesicles to sarcolemma (overexpression) during early sepsis but internalized from surface membranes to intracellular sites (underexpression) during late sepsis. Furthermore, changes in the receptor phosphorylation and gene transcription are responsible for the biphasic redistribution and the altered expression of m2AChR in the rat heart during the progression of sepsis.

KEYWORDS Gene expression; Muscarinic (ant)agonists; Protein phosphorylation; Receptors; Sarcolemma; Septic shock


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[Abstract] [Full Text] [PDF]


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