LEAD INDUCED CHANGES IN NITRIC OXIDE SIGNAL TRANSDUCTION

铅(Pb2+)引起神经功能障碍的潜在机制(S)与许多神经递质系统的功能障碍有关，导致神经传递功能障碍。然而，认知功能障碍与Pb2+暴露之间的关系仍不清楚。Pb2+暴露改变了在神经元发育和可塑性中起关键作用的钙稳态。最近的证据表明：(1)一氧化氮合酶(NOS)活性在突触可塑性中起关键作用；(2)一氧化氮合酶(NO)介导的一氧化碳(CO)和cGMP的生成以及cGMP依赖的蛋白激酶(PKG)活性可以通过环腺苷二磷酸核糖(CADPR)和肌醇1，4，5-三磷酸(InsP3)门控的钙通道来改变钙稳态。在体外，Pb2+可降低脑组织中一氧化氮合酶的活性，可能是由于铅引起的一氧化氮合酶活性和一氧化氮水平的降低导致了一氧化氮通过血红素加氧酶(HO-2)产生的改变、由可溶性鸟苷环化酶(SGC)产生的cGMP的改变以及细胞内钙离子的动员。需要检验的假设是，Pb2+暴露降低了NOS活性和NO水平，导致NO通过CO和cGMP介导的信号转导和钙稳态的调节，这在中枢神经系统的发育中起着至关重要的作用，导致认知功能障碍。为了验证上述假设，本研究旨在评估Pb2+暴露对：(1)NOS和HO-2活性，(2)作为NO和CO靶标的sGC活性，(3)cGMP水平，(4)dGMP依赖的蛋白激酶(PKG)活性，(5)cADPR和InsP3水平，以及(6)依赖cADPR和InsP3的钙释放的影响，以及PKG介导的磷酸化对它们的调节。

The underlying mechanism(s) of neurological disorders caused by lead (Pb2+) have been correlated to the disruption of functioning of a number of neurotransmitter systems leading to impairment of neural transmission. However, the relationship between cognitive dysfunction and Pb2+ exposure is still unclear. Pb2+ exposure alters Ca2+ homeostasis which plays a critical role in neuronal development and plasticity. Recent evidence suggests that (1) nitric oxide synthase (NOS) activity plays a pivotal role in synaptic plasticity, and (2) nitric oxide (NO)-mediated carbon monoxide (CO) and cGMP generation and cGMP-dependent protein kinase (PKG) activity can alter Ca2+ homeostasis via cyclic ADP ribose (cADPR)- and inositol 1,4,5-triphosphate (InsP3)-gated Ca2+ channels. Pb2+, in vitro, decreases NOS activity of brain, and it is likely that Pb(2+)- induced decrease in NOS activity and NO levels leads to changes in NO-mediated CO generation by heme oxygenase (HO-2), cGMP generation by soluble guanylate cyclase (sGC), and mobilization of intracellular Ca2+. The hypothesis to be tested is that Pb2+ exposure decreases NOS activity and NO levels resulting in the modulation of NO-mediated signal transduction via CO and cGMP, and Ca2+ homeostasis, which play a crucial role during the development of the central nervous system, leading to cognitive dysfunction. To test the above hypothesis, the present study is proposed to assess the effect of Pb2+ exposure on: (1) NOS and HO-2 activity, (2) sGC activity, a target for NO and CO, (3) cGMP levels, (4) dGMP-dependent protein kinase (PKG) activity, (5) cADPR and InsP3 levels, and (6) cADPR- and InsP3-dependent Ca2+ release and their modulation by PKG- mediated phosphorylation.