Copani A, Bruno V M, Barresi V, Battaglia G, Condorelli D F, Nicoletti F
Institute of Pharmacology and Biochemistry, School of Medicine, University of Catania, Italy.
J Neurochem. 1995 Jan;64(1):101-8. doi: 10.1046/j.1471-4159.1995.64010101.x.
Cultured granule cells grown in serum-containing medium with a "low K+" concentration (10 mM) underwent apoptosis after maturation for 5 days in vitro (5 DIV), a time that coincides with the developmental decline in the activity of metabotropic glutamate receptors (mGluRs) coupled to polyphosphoinositide hydrolysis. The mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) prevented the development of low K(+)-induced apoptosis and the presence of the drug was critical at 6 and 7 DIV, i.e., after the drop of mGluR activity. The neuroprotective action of 1S,3R-ACPD was prevented by the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) and was mimicked by N-methyl-D-aspartate or carbamylcholine but not by agonists of the mGluR subtypes negatively linked to adenylyl cyclase. In cultures treated either with Li(+)-which reduced polyphosphoinositide response to concentrations of glutamate (5 microM) that approximate those physiologically present in the incubation medium--or MCPG, the development of low K(+)-induced apoptosis already occurred at 4 DIV. Thus, the activation of mGluRs coupled to polyphosphoinositide hydrolysis by endogenous glutamate could contribute to protect cultured granule cells against apoptosis during early stages of maturation.
在含血清培养基中以“低钾”浓度（10 mM）培养的颗粒细胞，在体外成熟5天（5日龄）后发生凋亡，这个时间与代谢型谷氨酸受体（mGluRs）与多磷酸肌醇水解偶联活性的发育性下降相吻合。mGluR激动剂（1S,3R）-1-氨基环戊烷-1,3-二羧酸（1S,3R-ACPD）可防止低钾诱导的凋亡发生，且该药物在6日龄和7日龄时（即mGluR活性下降后）的存在至关重要。mGluR拮抗剂（RS）-α-甲基-4-羧基苯甘氨酸（MCPG）可阻断1S,3R-ACPD的神经保护作用，N-甲基-D-天冬氨酸或氨甲酰胆碱可模拟其作用，但与腺苷酸环化酶负相关的mGluR亚型激动剂则不能模拟。在用锂（降低多磷酸肌醇对接近孵育培养基中生理浓度的谷氨酸（5 microM）的反应）或MCPG处理的培养物中，低钾诱导的凋亡在4日龄时就已发生。因此，内源性谷氨酸对与多磷酸肌醇水解偶联的mGluRs的激活可能有助于在成熟早期保护培养的颗粒细胞免受凋亡。
