Amino Acid Changes at Arginine 204 of Troponin I Result in Increased Calcium Sensitivity of Force Development.
Amino Acid Changes at Arginine 204 of Troponin I Result in Increased Calcium Sensitivity of Force Development.
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DOI：
10.3389/fphys.2016.00520
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发表时间：
2016
影响因子：
4
通讯作者：
Gomes AV
中科院分区：
文献类型：
--
作者：
Nguyen S;Siu R;Dewey S;Cui Z;Gomes AV
人心肌肌钙蛋白I（cTnI）突变与限制性、扩张性和肥厚性心肌病相关。与家族性肥厚型心肌病（FHC）相关的cTnI上最常见的残基是精氨酸（R），这也是发生多种突变的最常见残基。已知在cTnI精氨酸204处发生两种FHC突变，R204 C和R204 H，并且两者都与不良临床预后相关。R204 H突变也与限制性心肌病（RCM）有关。为了表征同一残基（R204）上的不同突变对cTnI生理功能的影响，在带皮纤维研究中研究了R204处的6个突变（C、G、H、P、Q、W）。皮纤维研究表明，与野生型（WT）cTnI相比，R204处的所有检测突变均导致力发展的Ca 2+敏感性显著增加（Δ pCa 50 = 0.22-0.35）。cTnI突变体与WT心肌肌钙蛋白C（cTnC）或WT心肌肌钙蛋白T（cTnT）之间相互作用的研究表明，除R204 G外，所有研究的突变均影响cTnI：cTnT和cTnI：cTnC相互作用中的一种或两种。R204 H突变影响cTnI：cTnT和cTnI：cTnC相互作用，而R204 C突变仅影响cTnI：cTnC相互作用。这些结果表明，cTnI上相同位点的不同突变可能对细丝相互作用产生不同的影响。快速骨骼肌肌钙蛋白I（R174 Q，与cTnI R204 Q同源）的突变也显著增加了力发展的钙敏感性（Δ pCa 50 = 0.16）。我们的研究表明，已知的cTnI突变与预后不良（R204 C和R204 H）表现出大幅度增加的Ca 2+敏感性的力量发展。因此，其他引起Ca 2+敏感性类似增加的R204突变也可能具有较差的遗传性。
Mutations in human cardiac troponin I (cTnI) have been associated with restrictive, dilated, and hypertrophic cardiomyopathies. The most commonly occurring residue on cTnI associated with familial hypertrophic cardiomyopathy (FHC) is arginine (R), which is also the most common residue at which multiple mutations occur. Two FHC mutations are known to occur at cTnI arginine 204, R204C and R204H, and both are associated with poor clinical prognosis. The R204H mutation has also been associated with restrictive cardiomyopathy (RCM). To characterize the effects of different mutations at the same residue (R204) on the physiological function of cTnI, six mutations at R204 (C, G, H, P, Q, W) were investigated in skinned fiber studies. Skinned fiber studies showed that all tested mutations at R204 caused significant increases in Ca2+ sensitivity of force development (ΔpCa50 = 0.22–0.35) when compared to wild-type (WT) cTnI. Investigation of the interactions between the cTnI mutants and WT cardiac troponin C (cTnC) or WT cardiac troponin T (cTnT) showed that all the mutations investigated, except R204G, affected either or both cTnI:cTnT and cTnI:cTnC interactions. The R204H mutation affected both cTnI:cTnT and cTnI:cTnC interactions while the R204C mutation affected only the cTnI:cTnC interaction. These results suggest that different mutations at the same site on cTnI could have varying effects on thin filament interactions. A mutation in fast skeletal TnI (R174Q, homologous to cTnI R204Q) also significantly increased Ca2+ sensitivity of force development (ΔpCa50 = 0.16). Our studies indicate that known cTnI mutations associated with poor prognosis (R204C and R204H) exhibit large increases in Ca2+ sensitivity of force development. Therefore, other R204 mutations that cause similar increases in Ca2+ sensitivity are also likely to have poor prognoses.
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通讯作者：
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影响因子：
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