Wang Xiaojing, Levic Snezana, Gratton Michael Anne, Doyle Karen Jo, Yamoah Ebenezer N, Pegg Anthony E
Department of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
J Biol Chem. 2009 Jan 9;284(2):930-7. doi: 10.1074/jbc.M807758200. Epub 2008 Nov 10.
Male gyro (Gy) mice, which have an X chromosomal deletion inactivating the SpmS and Phex genes, were found to be profoundly hearing impaired. This defect was due to alteration in polyamine content due to the absence of spermine synthase, the product of the SpmS gene. It was reversed by breeding the Gy strain with CAG/SpmS mice, a transgenic line that ubiquitously expresses spermine synthase under the control of a composite cytomegalovirus-IE enhancer/chicken beta-actin promoter. There was an almost complete loss of the endocochlear potential in the Gy mice, which parallels the hearing deficiency, and this was also reversed by the production of spermine from the spermine synthase transgene. Gy mice showed a striking toxic response to treatment with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO). Within 2-3 days of exposure to DFMO in the drinking water, the Gy mice suffered a catastrophic loss of motor function resulting in death within 5 days. This effect was due to an inability to maintain normal balance and was also prevented by the transgenic expression of spermine synthase. DFMO treatment of control mice or Gy-CAG/SpmS had no effect on balance. The loss of balance in Gy mice treated with DFMO was due to inhibition of polyamine synthesis because it was prevented by administration of putrescine. Our results are consistent with a critical role for polyamines in regulation of Kir channels that maintain the endocochlear potential and emphasize the importance of normal spermidine:spermine ratio in the hearing and balance functions of the inner ear.
雄性陀螺（Gy）小鼠在X染色体上存在缺失，导致SpmS和Phex基因失活，被发现有严重的听力障碍。这种缺陷是由于缺乏精胺合酶（SpmS基因的产物）导致多胺含量改变所致。通过将Gy品系与CAG/SpmS小鼠杂交，这种缺陷得以逆转，CAG/SpmS小鼠是一种转基因品系，在复合巨细胞病毒-IE增强子/鸡β-肌动蛋白启动子的控制下普遍表达精胺合酶。Gy小鼠的内淋巴电位几乎完全丧失，这与听力缺陷平行，而精胺合酶转基因产生的精胺也使其得到逆转。Gy小鼠对鸟氨酸脱羧酶抑制剂α-二氟甲基鸟氨酸（DFMO）的治疗表现出明显的毒性反应。在饮用水中接触DFMO的2 - 3天内，Gy小鼠的运动功能遭受灾难性损失，导致在5天内死亡。这种效应是由于无法维持正常平衡，并且精胺合酶的转基因表达也可预防这种情况。用DFMO处理对照小鼠或Gy-CAG/SpmS小鼠对平衡没有影响。用DFMO处理的Gy小鼠平衡丧失是由于多胺合成受到抑制，因为给予腐胺可预防这种情况。我们的结果与多胺在调节维持内淋巴电位的Kir通道中起关键作用一致，并强调了正常亚精胺：精胺比例在内耳听力和平衡功能中的重要性。
