AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by beh...AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests,and the molecular mechanisms were investigated by patch-clamp experiments.RESULTS:The loss of Celsr3 led to ataxia-like behavior,accompanied by impaired miniature excitatory postsynaptic currents(mEPSCs)and postsynaptic long-term potentiation(LTP)in PCs.The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice.Interestingly,the effects of forskolin could be blocked by SQ22536(a cAMP antagonist)and ESI-08(exchange protein activated by cAMP antagonist;Epac)but the H89(a PKA antagonist)could not block the effects.CONCLUSION:Celsr3 plays an important role in motor coordination by modulating synaptic function,and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.展开更多
由cAMP激活的交换蛋白分子(exchange protein activated by c AMP,Epac)是近年来新发现的鸟嘌呤核苷酸交换因子,参与一系列cAMP介导的信号通路。纤维化疾病是临床上常见的一类疾病,是在正常生理学(如衰老)或不同致病因素持续刺激下,使...由cAMP激活的交换蛋白分子(exchange protein activated by c AMP,Epac)是近年来新发现的鸟嘌呤核苷酸交换因子,参与一系列cAMP介导的信号通路。纤维化疾病是临床上常见的一类疾病,是在正常生理学(如衰老)或不同致病因素持续刺激下,使得细胞外基质过度沉积的结果。有研究表明,Epac在纤维化疾病中发挥重要作用,因此,该文对Epac在纤维化疾病中的作用进行综述,以促进对于Epac相关机制及药物的研究与开发。展开更多
基金Supported by the Natural Science Foundation of Chongqing Municipality,China(No.CSTB2022NSCQ-BHX0725)the National Natural Science Foundation of China(No.82401728).
文摘AIM:To evaluate the function and mechanisms of forskolin in treating ataxia-like behavior in Celsr3 conditional knockout(cKO)mice.METHODS:The efficiency of intraperitoneally administered forskolin was evaluated by behavioral tests,and the molecular mechanisms were investigated by patch-clamp experiments.RESULTS:The loss of Celsr3 led to ataxia-like behavior,accompanied by impaired miniature excitatory postsynaptic currents(mEPSCs)and postsynaptic long-term potentiation(LTP)in PCs.The cAMP activator forskolin ameliorated ataxia-like behavior and abrogated the mEPSCs impairment and LTP in model mice.Interestingly,the effects of forskolin could be blocked by SQ22536(a cAMP antagonist)and ESI-08(exchange protein activated by cAMP antagonist;Epac)but the H89(a PKA antagonist)could not block the effects.CONCLUSION:Celsr3 plays an important role in motor coordination by modulating synaptic function,and forskolin may be a valuable therapeutic drug for certain types of inherited cerebellar ataxia.
文摘由cAMP激活的交换蛋白分子(exchange protein activated by c AMP,Epac)是近年来新发现的鸟嘌呤核苷酸交换因子,参与一系列cAMP介导的信号通路。纤维化疾病是临床上常见的一类疾病,是在正常生理学(如衰老)或不同致病因素持续刺激下,使得细胞外基质过度沉积的结果。有研究表明,Epac在纤维化疾病中发挥重要作用,因此,该文对Epac在纤维化疾病中的作用进行综述,以促进对于Epac相关机制及药物的研究与开发。
