Furukawa K, Mattson M P
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536, USA.
Neuroscience. 1998 Mar;83(2):429-38. doi: 10.1016/s0306-4522(97)00398-9.
The secreted form of beta-amyloid precursor protein (sAPP alpha) is released from neurons in an activity-dependent manner; data suggest sAPP alpha may play roles in regulating neuronal excitability, plasticity, and survival. In cultured hippocampal neurons sAPP alpha can suppress elevation of [Ca2+]i induced by glutamate and can protect neurons against excitotoxicity. We now report whole-cell patch-clamp data from studies of cultured embryonic rat hippocampal neurons which demonstrate that sAPP alpha selectively suppresses N-methyl-D-aspartate currents without affecting currents induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate or kainate. sAPP alpha suppressed N-methyl-D-aspartate current rapidly and reversibly at concentrations of 0.011 nM. Suppression of N-methyl-D-aspartate current by sAPP alpha is apparently mediated by cyclic guanosine monophosphate because 8-bromo-cyclic guanosine monophosphate suppressed N-methyl-D-aspartate current in a manner similar to sAPP alpha, and two different inhibitors of cyclic guanosine monophosphate-dependent protein kinase prevented sAPP alpha-induced suppression of N-methyl-D-aspartate current. In addition, okadaic acid prevented suppression of N-methyl-D-aspartate-induced current suggesting the involvement of a protein phosphatase in modulation of N-methyl-D-aspartate current by sAPP alpha. These data identify a mechanism whereby sAPP alpha can modulate cellular responses to glutamate, and suggest important roles for sAPP alpha in the various physiological and pathophysiological processes in which N-methyl-D-aspartate receptors participate.
β-淀粉样前体蛋白的分泌形式（sAPPα）以活性依赖的方式从神经元中释放；数据表明sAPPα可能在调节神经元兴奋性、可塑性和存活中发挥作用。在培养的海马神经元中，sAPPα可以抑制谷氨酸诱导的[Ca2+]i升高，并能保护神经元免受兴奋毒性。我们现在报告来自培养的胚胎大鼠海马神经元研究的全细胞膜片钳数据，这些数据表明sAPPα选择性地抑制N-甲基-D-天冬氨酸电流，而不影响由α-氨基-3-羟基-5-甲基异恶唑-4-丙酸或海人藻酸诱导的电流。sAPPα在0.011 nM的浓度下迅速且可逆地抑制N-甲基-D-天冬氨酸电流。sAPPα对N-甲基-D-天冬氨酸电流的抑制显然是由环磷酸鸟苷介导的，因为8-溴环磷酸鸟苷以类似于sAPPα的方式抑制N-甲基-D-天冬氨酸电流，并且两种不同的环磷酸鸟苷依赖性蛋白激酶抑制剂阻止了sAPPα诱导的N-甲基-D-天冬氨酸电流抑制。此外，冈田酸阻止了N-甲基-D-天冬氨酸诱导电流的抑制，表明蛋白磷酸酶参与了sAPPα对N-甲基-D-天冬氨酸电流的调节。这些数据确定了一种sAPPα可以调节细胞对谷氨酸反应的机制，并表明sAPPα在N-甲基-D-天冬氨酸受体参与的各种生理和病理生理过程中具有重要作用。
