Development of prevention and therapy against xerostomia

最近，日本出现口干症症状的患者迅速增加。然而，唾液腺功能障碍的机制还不是很清楚，我们利用药物诱导的实验模型来研究这一机制，以寻找改善口干症状况的药物，并获得了如下结果。大鼠唾液腺对β_2激动剂诱导的分泌反应改变的机制：用β_2激动剂短期处理组织，可导致组织对激动剂反应的蛋白质分泌减敏，这与β_2受体密度和受体对激动剂的亲和力降低有关。这种现象伴随着蛋白磷酸酶(PP)2A脱磷引起的Gi2Alpha蛋白功能的增强，但并不伴随Gi2Alpha和Gsalpha蛋白…含量的变化免疫印迹分析更能说明问题。结论：1.用PP2A抑制剂对组织进行预处理，完全阻断了Gi2α蛋白功能的增强，使蛋白分泌的脱敏作用消失。乙酰胆碱(ACh)和SNI-201诱导大鼠唾液腺泡细胞水通道蛋白5(AQP5)转位的调节机制。用AQP5蛋白抗血清识别细胞顶膜和细胞内膜上的水通道。ACh和SNI-2011均作用于M_3受体，并将AQP5从ICM移位到APM。AQP5对促分泌剂的反应时程显示，SNI-2011诱导的AQP5移位持续时间超过30min，而ACh诱导的AQP5移位在10min时不再明显。在新霉素或TMB-8处理的组织中，没有观察到分泌剂诱导的AQP5的移位。这一结果表明，PP2A和SNI-2011的抑制剂有可能改善口干症的状况。较少

Recently, patients who have symptoms of xerostomia increased rapidly in Japan. However, the mechanisms underlying the dysfunction of salivary glands has not been dear, We investigated this mechanisms using the drug-induced experimental models to find drugs to improve the condition of xerostomia and obtained the results described as follows.1. Mechanisms underlying the alteration of secretory response of rat salivary glands to beta_2 agonist induced by the pretreatment of the agonist.Short-term treatment of the tissues with beta_2 agonist resulted in the desensitization of protein secretion from the tissues in response to the agonist, which was coupled with the decrease in beta_2 receptor density and the affinity of the receptor for the agonist. The phenomenon was followed by the enhancement of Gi2alpha protein function caused by the dephophorylation of the protein with protein phosphatase(PP)2A, but was not accompanied by the changes in the amounts of Gi2alpha and Gsalpha proteins asse … More ssed by immunoblot analysis. Pretreatment of the tissues with PP2A inhibitors completely blocked the enhancement of Gi2alpha protein function and resulted in the disappearance of the desensitization of protein secretion.2. Regulatory mechanisms of translocation of aquaporin(AQP)5 in rat salivary acinar cells induced by acetylchorine(ACh) and SNI-2011.AQP5 water channel was recognized in apical plasma membranes(APM) and intracellular membranes(ICM) in the cells using the specific anti-AQP5 protein antiserum. Both ACh and SNI-2011 acted at M_3 muscarinic receptors and translocated AQP5 from ICM to APM.The time course of the response of AQP5 to the secretagogues revealed that the translocation of AQP5 induced by SNI-2011 persisted longer than 30min, but that by ACh was no longer apparent at 10min. The translocation of AQP5 induced by the secretagogues was not observed in the tissues treated with neomycin or TMB-8.These findings indicate that inhibitors of PP2A and SNI-2011 have the possibilities to improve the condition of xerostomia. Less