Huang C C, Liang Y C, Hsu K S
Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan City, Taiwan 701, Republic of China.
J Biol Chem. 2001 Dec 21;276(51):48108-17. doi: 10.1074/jbc.M106388200. Epub 2001 Oct 25.
Reversal of long term potentiation (LTP) may function to increase the flexibility and storage capacity of neuronal circuits; however, the underlying mechanisms remain incompletely understood. We show that depotentiation induced by low frequency stimulation (LFS) (2 Hz, 10 min, 1200 pulses) was input-specific and dependent on N-methyl-d-aspartate (NMDA) receptor activation. The ability of LFS to reverse LTP was mimicked by a brief application of NMDA. This NMDA-induced depotentiation was blocked by adenosine A(1) receptor antagonist. However, the reversal of LTP by LFS was unaffected by metabotropic glutamate receptor antagonism. This LFS-induced depotentiation was specifically prevented by protein phosphatase (PP)1 inhibitors, okadaic acid, and calyculin A but not by the PP2A or PP2B inhibitors. Furthermore, by using phosphorylation site-specific antibodies, we found that LFS-induced depotentiation is associated with a persistent dephosphorylation of the GluR1 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor at serine 831, a protein kinase C and calcium/calmodulin-dependent protein kinase II (CaMKII) substrate, but not at serine 845, a substrate of cAMP-dependent protein kinase. This effect was mimicked by bath-applied adenosine or NMDA and was specifically prevented by okadaic acid. Also, the increased phosphorylation of CaMKII at threonine 286 and the decreased PP activity seen with LTP were overcome by LFS, adenosine, or NMDA application. These results suggest that LFS erases LTP through an NMDA receptor-mediated activation of PP1 to dephosphorylate amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and CaMKII in the CA1 region of the hippocampus.
长时程增强（LTP）的逆转可能起到增强神经回路灵活性和存储容量的作用；然而，其潜在机制仍未完全明确。我们发现，低频刺激（LFS，2赫兹，10分钟，1200个脉冲）诱导的去增强作用具有输入特异性，且依赖于N-甲基-D-天冬氨酸（NMDA）受体激活。短暂应用NMDA可模拟LFS逆转LTP的能力。这种NMDA诱导的去增强作用被腺苷A(1)受体拮抗剂阻断。然而，LFS对LTP的逆转不受代谢型谷氨酸受体拮抗剂的影响。LFS诱导的去增强作用可被蛋白磷酸酶（PP）1抑制剂冈田酸和花萼海绵诱癌素A特异性阻断，但不受PP2A或PP2B抑制剂影响。此外，通过使用位点特异性磷酸化抗体，我们发现LFS诱导的去增强作用与丝氨酸831位点的3-羟基-5-甲基-4-异恶唑丙酸受体（AMPA受体）GluR1亚基持续去磷酸化有关，丝氨酸831是蛋白激酶C和钙/钙调蛋白依赖性蛋白激酶II（CaMKII）的底物，而丝氨酸845位点（环磷酸腺苷依赖性蛋白激酶的底物）则未出现这种情况。这种效应可被浴用腺苷或NMDA模拟，并被冈田酸特异性阻断。同样，LFS、腺苷或NMDA的应用可克服LTP时出现的苏氨酸286位点CaMKII磷酸化增加和PP活性降低的情况。这些结果表明，LFS通过NMDA受体介导的PP1激活，使海马体CA1区的AMPA受体和CaMKII去磷酸化，从而消除LTP。
