Sanyal Subhabrata, Jennings Tricia, Dowse Harold, Ramaswami Mani
Molecular and Cellular Biology Department and ARL Division of Neurobiology, University of Arizona, 1007 E. Lowell Street, Life Sciences South, AZ, Tucson, USA.
J Comp Physiol B. 2006 Mar;176(3):253-63. doi: 10.1007/s00360-005-0046-7. Epub 2005 Dec 1.
To analyze the role of cytosolic calcium in regulating heart beat frequency and rhythm, we studied conditional mutations in Drosophila Sarco-endoplasmic reticulum Ca2+-ATPase, believed to be predominantly responsible for sequestering free cytosolic calcium. Abnormalities in the amount or structure of the SERCA protein have been linked to cardiac malfunction in mammals. Drosophila SERCA protein (dSERCA) is highly enriched in Drosophila larval heart with a distinct membrane distribution of SERCA at cardiac Z-lines, suggesting evolutionarily conserved zones for calcium uptake into the sarcoplasmic reticulum. Heart beat frequency is strikingly reduced in mutant animals following dSERCA inactivation, (achieved by a brief exposure of these conditional mutants to non-permissive temperature). Cardiac contractions also show abnormal rhythmicity and electrophysiological recordings from the heart muscle reveal dramatic alterations in electrical activity. Overall, these studies underscore the utility of the Drosophila heart to model SERCA dysfunction dependent cardiac disorders and constitute an initial step towards developing Drosophila as a viable genetic model system to study conserved molecular determinants of cardiac physiology.
为了分析胞质钙在调节心跳频率和节律中的作用，我们研究了果蝇肌浆网钙ATP酶（Sarco-endoplasmic reticulum Ca2+-ATPase）的条件性突变，该酶被认为主要负责隔离游离的胞质钙。SERCA蛋白的数量或结构异常与哺乳动物的心脏功能障碍有关。果蝇SERCA蛋白（dSERCA）在果蝇幼虫心脏中高度富集，在心脏Z线处SERCA具有独特的膜分布，这表明存在进化上保守的将钙摄取到肌浆网的区域。在dSERCA失活后（通过将这些条件性突变体短暂暴露于非允许温度来实现），突变动物的心跳频率显著降低。心脏收缩也表现出异常的节律性，并且来自心肌的电生理记录显示电活动发生了显著改变。总体而言，这些研究强调了果蝇心脏作为模拟SERCA功能障碍依赖性心脏疾病模型的实用性，并构成了将果蝇发展成为研究心脏生理学保守分子决定因素的可行遗传模型系统的第一步。
