Zhuo M, Laitinen J T, Li X C, Hawkins R D
Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia, Howard Hughes Medical Institute, New York, New York 10032, USA.
Learn Mem. 1998 Nov-Dec;5(6):467-80.
Perfusion of hippocampal slices with an inhibitor of nitric oxide (NO) synthase-blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.
用一氧化氮（NO）合酶抑制剂灌注海马切片，可阻断单串强直刺激诱导的长时程增强（LTP），并显著降低双串强直刺激诱导的LTP，但对四串强直刺激诱导的LTP仅有轻微降低。血红素加氧酶（一氧化碳（CO）的合成酶）抑制剂可显著降低双串或四串强直刺激诱导的LTP。这些结果表明，NO和CO都参与LTP，但可能发挥不同的作用。一种可能性是，NO起阶段性信号作用，而CO提供持续性背景刺激。另一种可能性是，NO和CO在不同情况下被阶段性激活，可能涉及不同的受体和第二信使。由于已知在强直刺激期间NO通过NMDA受体的刺激而被激活，我们研究了CO可能通过代谢型谷氨酸受体（mGluRs）的刺激而被激活的可能性。与这一观点一致，mGluR激动剂tACPD诱导的持久增强被血红素加氧酶抑制剂阻断，但未被NO合酶抑制剂阻断。tACPD诱导的增强也被可溶性鸟苷酸环化酶（NO和CO的共同靶点）或cGMP依赖性蛋白激酶的抑制剂阻断，并且鸟苷酸环化酶在海马切片中被tACPD激活。然而，生化分析表明，虽然血红素加氧酶在海马中组成性激活，但它似乎未被强直刺激或tACPD刺激。这些结果最符合以下可能性，即组成性（持续性）而非刺激（阶段性）的血红素加氧酶活性对于强直刺激或tACPD诱导的增强是必需的，并表明mGluR激活通过其他途径阶段性刺激鸟苷酸环化酶。
