Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea
Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea
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DOI：
10.1074/jbc.m213176200
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发表时间：
2003-05-16
影响因子：
4.8
通讯作者：
Greer, JJ
中科院分区：
文献类型：
--
作者：
Berry, GT;Wu, S;Greer, JJ
肌醇（Ins）及其多磷酸肌醇衍生物在膜信号传导中起重要作用，长期以来一直被认为在脑代谢中起特殊作用。由于聚磷酸肌醇迅速转变，并且在神经组织中异常丰富，因此在脑中观察到的2-15 mM范围内的高Ins水平可能是维持神经元内不同膜位置的磷酸肌醇合成速率所必需的。这种幅度的细胞浓度梯度表明依赖于主动Ins运输，特别是在生长和分化的时候。Na+/肌醇协同转运蛋白（SMIT 1或SLC 5A 3）基因在产前中枢神经系统和胎盘中高度表达。为了更深入地了解大脑Ins代谢，同时确定SMIT 1作为转运蛋白的重要性，我们产生了该基因纯合靶向缺失的小鼠。新生的SMIT 1（-/-）动物没有SMIT 1 mRNA的证据，脑Ins水平降低92%，全身Ins降低84%，并且在出生后不久由于换气不足而死亡。近足月妊娠胎龄18.5天胎儿的各器官以及胎盘的大体病理和光镜检查均正常。基于[H-3]乙酸盐掺入肺组织外植体的磷脂中，肺组织表面活性蛋白A、B和C的免疫染色，以及肺泡细胞的电子显微镜检查，没有证据表明肺中2型肺细胞产生异常的肺表面活性物质。虽然在神经系统中未检测到组织学病变，但对脑干前Botzinger呼吸控制中心的电生理研究显示了异常节律放电伴中枢性呼吸暂停。死亡原因可以解释为脑干通气控制的调节缺陷。该模型证明了SMIT 1在神经系统发育中的重要性。高亲和力SMIT 1转运蛋白负责小鼠胎儿-胎盘单位中的Ins浓度梯度。
myo-Inositol (Ins) and its polyphosphoinositide derivatives that are important in membrane signaling have long been held to play a special role in brain metabolism. As polyphosphoinositides turn over rapidly and are exceptionally abundant in nervous tissue, high Ins levels in the range of 2-15 mM that have been observed in brain may be necessary to maintain the rates of phosphoinositide synthesis in diverse membrane locations within neurons. Cellular concentration gradients of this magnitude indicate a dependence on active Ins transport, especially at the time of growth and differentiation. The Na+/myo-inositol cotransporter (SMIT1 or SLC5A3) gene is highly expressed prenatally in the central nervous system and placenta. To gain more insight into brain Ins metabolism, while ascertaining the importance of SMIT1 as a transporter, we generated mice with a homozygous targeted deletion of this gene. Newborn SMIT1(-/-) animals have no evidence of SMIT1 mRNA, a 92% reduction in the level of brain Ins, an 84% reduction in whole body Ins, and expire shortly after birth due to hypoventilation. Gross pathologic and light microscopic examinations of each organ, as well as the placenta, of embryonic day 18.5 fetuses at near term gestation were normal. Based on [H-3] acetate incorporation into phospholipids of lung tissue explants, immunostaining of lung tissue for surfactant protein A, B, and C, and electron microscopic examination of alveolar cells, there was no evidence of abnormal pulmonary surfactant production by type 2 pneumocytes in lung. Although no histologic lesions were detected in the nervous system, electrophysiological studies of the brainstem pre-Botzinger respiratory control center demonstrated an abnormal rhythm discharge with periods of central apnea. The cause of death can be explained by the regulatory defect in brainstem control of ventilation. This model demonstrates the critical importance of SMIT1 in the developing nervous system. The high affinity SMIT1 transporter is responsible for the Ins concentration gradient in the murine fetal-placental unit.