A switch that lowers the betaAR: insights from a troponin I mutation linked to hypertrophic cardiomyopathy.
A switch that lowers the betaAR: insights from a troponin I mutation linked to hypertrophic cardiomyopathy.
复制标题
降低 betaAR 的开关：来自与肥厚型心肌病相关的肌钙蛋白 I 突变的见解。
DOI：
10.1016/j.yjmcc.2005.06.014
复制
发表时间：
2006
影响因子：
5
通讯作者：
Westfall,MargaretV
中科院分区：
文献类型：
--
作者：
Westfall,MargaretV
Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by a defect in one of several genes [1, 2]. Over the last 15 years, significant knowledge has been gained about the heterogeneous nature and the mutant proteins responsible for the inherited form of this disorder [2, 3]. Mutations in sarcomeric proteins containing a genetic substitution and/or truncation make up a large portion of the mutants responsible for this disease [2, 3]. The development of hypertrophy and progression to heart failure in individuals with HCM typically involves re-expression of the fetal gene program, and results in alterations in cellular Ca2+ cycling [2]. In recent studies, investigators are beginning to focus on the alterations in, and the role of cell signaling pathways in HCM, including adrenergic signaling during the disease process [4, 5].In this issue of the Journal of Molecular and Cellular Cardiology, Gomes et al.[6] investigate changes in myofilament function resulting from a troponin I (TnI) substitution mutant linked to HCM. The Arg21Cys TnI mutation described in this study is of particular interest for several reasons. First, this mutation is present in the unique 32 amino acid extension of the cardiac isoform of TnI (cTnI). The role of this unique extension in the molecular switch function of cTnI is not well understood. Addition of the Arg21Cys mutant to permeabilized porcine papillary preparations after extraction of wildtype cTnI demonstrate that this extension influences the function of cTnI and the mutation enhances myofilament Ca2+ sensitivity under basal conditions. Another significant aspect of this extension is its targeted phosphorylation by protein kinase A (PKA)[7], and Arg21 is part of the consensus sequence for β-adrenergic activated PKA-mediated phosphorylation of cTnI [8]. In the present study, reduced phosphorylation of the mutant cTnI is observed in response to PKA, which is activated during the β-adrenergic signaling response. Thus, expression of this mutant may play an important role under basal conditions and during the β-adrenergic response (βAR) in the intact heart. Loss of β-adrenergic cTnI phosphorylation also is associated with increased proteolytic deg-
