Development of prevention and therapy against xerostomia

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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