Victor R G, Thomas G D, Marban E, O'Rourke B
Johns Hopkins University, Division of Cardiology, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6269-73. doi: 10.1073/pnas.92.14.6269.
Synaptic plasticity is modulated by Ca(2+)-induced alterations in the balance between phosphorylation and dephosphorylation. Recent evidence suggests that calcineurin, the Ca(2+)-calmodulin-dependent phosphatase (2B), modulates the activity of postsynaptic glutamate receptors. However, in rat cortex, calcineurin is enriched mainly in presynaptic, not postsynaptic, fractions. To determine if calcineurin modulates glutamatergic neurotransmission through a presynaptic mechanism, we used whole-cell patch clamp experiments to test effects of two specific calcineurin inhibitors, cyclosporin A (CsA) and FK506, on synaptic activity in fetal rat cortical neurons. The rate of spontaneous action-potential firing was markedly increased by either CsA or FK506 but was unaffected by rapamycin, a structural analog of FK506 which has no effect on calcineurin. In voltage-clamp experiments, CsA increased the rate but not the amplitude of glutamate receptor-mediated, excitatory postsynaptic currents, suggesting an increased rate of glutamate release. CsA had no effect on the amplitude of currents evoked by brief bath application of selective glutamate receptor agonists, providing further evidence for a pre- rather than postsynaptic site of action. In conclusion, these data indicate that calcineurin modulates glutamatergic neurotransmission in rat cortical neurons through a presynaptic mechanism.
突触可塑性受钙离子诱导的磷酸化和去磷酸化平衡变化的调节。最近的证据表明，钙调神经磷酸酶，即钙离子/钙调蛋白依赖性磷酸酶（2B），可调节突触后谷氨酸受体的活性。然而，在大鼠皮质中，钙调神经磷酸酶主要富集于突触前部分，而非突触后部分。为了确定钙调神经磷酸酶是否通过突触前机制调节谷氨酸能神经传递，我们使用全细胞膜片钳实验来测试两种特异性钙调神经磷酸酶抑制剂环孢菌素A（CsA）和FK506对胎鼠皮质神经元突触活性的影响。CsA或FK506均可显著增加自发动作电位发放率，但雷帕霉素（一种对钙调神经磷酸酶无作用的FK506结构类似物）对其无影响。在电压钳实验中，CsA增加了谷氨酸受体介导的兴奋性突触后电流的频率，但未改变其幅度，提示谷氨酸释放速率增加。CsA对短暂浴用选择性谷氨酸受体激动剂诱发的电流幅度无影响，这为其作用于突触前而非突触后部位提供了进一步证据。总之，这些数据表明钙调神经磷酸酶通过突触前机制调节大鼠皮质神经元的谷氨酸能神经传递。
