Adenylyl cyclase type 6 deletion decreases left ventricular function via impaired calcium handling
Adenylyl cyclase type 6 deletion decreases left ventricular function via impaired calcium handling
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DOI：
10.1161/circulationaha.107.730069
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发表时间：
2008-01-01
期刊：
影响因子：
37.8
通讯作者：
Hammond, H. Kirk
中科院分区：
文献类型：
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作者：
Tang, Tong;Gao, Mei Hua;Hammond, H. Kirk
背景 - 腺苷酸环化酶（ACs）是G蛋白偶联受体的一类效应分子。在心肌细胞中表达量最丰富的两种AC是5型（AC5）和6型（AC6），它们具有65%的氨基酸同源性。据推测，心肌细胞中两种AC类型的共表达代表一种冗余，但AC6在心脏生理学中的具体作用及其与AC5的差异仍有待明确。
方法与结果 - 我们培育了AC6靶向缺失的转基因小鼠。AC6缺失与左心室收缩功能（P = 0.026）和舒张功能（P = 0.041）降低有关。AC6缺失与心肌细胞中β - 肾上腺素能受体刺激的环磷腺苷（cAMP）生成减少48%（P = 0.003）以及蛋白激酶A活性降低（P = 0.015）有关。此外，受磷蛋白磷酸化降低（P = 0.015），肌浆网Ca²⁺ - ATP酶活性受损（P < 0.0001），并且心肌细胞在钙瞬变形成方面表现出明显异常（P = 0.001）。
结论 - AC6缺失导致的心脏cAMP生成受损和钙处理异常是左心室功能异常的基础。AC6缺失的生化和生理后果表明它是成年心脏中的一种重要效应分子，具有AC5无法复制的独特生物学功能。
Background-Adenylyl cyclases (ACs) are a family of effector molecules for G-protein - coupled receptors. The 2 ACs most abundantly expressed in cardiac myocytes are types 5 (AC5) and 6 (AC6), which have 65% amino acid homology. It has been speculated that coexpression of 2 AC types in cardiac myocytes represents redundancy, but the specific role of AC6 in cardiac physiology and its differences from AC5 remain to be defined.Methods and Results-We generated transgenic mice with targeted deletion of AC6. Deletion of AC6 was associated with reduced left ventricular contractile function (P = 0.026) and relaxation (P = 0.041). The absence of AC6 was associated with a 48% decay in beta-adrenergic receptor-stimulated cAMP production in cardiac myocytes (P = 0.003) and reduced protein kinase A activity (P = 0.015). In addition, phospholamban phosphorylation was reduced (P = 0.015), sarcoplasmic reticulum Ca2+-ATPase activity was impaired (P < 0.0001), and cardiac myocytes showed marked abnormalities in calcium transient formation (P = 0.001).Conclusions-The combination of impaired cardiac cAMP generation and calcium handling that result from AC6 deletion underlies abnormalities in left ventricular function. The biochemical and physiological consequences of AC6 deletion reveal it to be an important effector molecule in the adult heart, serving unique biological functions not replicated by AC5.