Neuropathy target esterase (NTE) was identified as the primary target of the organophosphorus compounds (OP) that cause a syndrome calledOP-induced delayed neuropathy (OPIDN), characterized by paralysis of the lower limbs due to degeneration of long axons in the spinal cord and peripheral nerves. It has been suggested that the inhibition and subsequent ageing of NTE initiates OPIDN.

Neuropathy target esterase (NTE), a membrane protein localized to endoplasmic reticulum, is characterized as a novel phospholipase B, and plays an important role in the development of embryo and neuron. Previous studies showed that the N-terminal regulatory part of NTE contained three putative cyclic AMP (cAMP)- binding sites, and those of which might have the ability of binding cAMP constituting a putative regulatory domain, indicating that NTE may be regulated by cAMP.

Professor Yi-Jun Wu and his team (Laboratory of Molecular Toxicology in the Institute of Zoology, Chinese Academy of Sciences) investigated the role of cAMP in the regulation of NTE in mammalian cells. The results demonstrated that activity of NTE-tagged with green fluorescent protein was not affected by cAMP in the COS7 and HEK293T cells. However, endogenous NTE activity, NTE protein and its mRNA levels were increased by elevating cAMP levels in the cells treated with dibutyryl cAMP, forskolin, or forskolin plus 1-isobutyl-3-methylxanthine (IBMX), and was decreased with adenyl cyclase inhibitors SQ22536. However, after pretreated with 30 μM cycloheximide, a protein synthesis inhibitor, no change of NTE activity was found in the above chemicals-treated cells. Treatment with H89, a protein kinase A (PKA) inhibitor, significantly decreased NTE activity, NTE protein and mRNA level; Moreover, effect of forskolin on NTE activity, NTE protein and mRNA levels were blocked by pretreatment with H89, indicating that regulation of NTE by cAMP was PKA-dependent. In addition, changes in GPC, but not PC, levels were correlated with the alteration of NTE activity induced by cAMP levels. These results provided evidence for the first time that cAMP/PKA signals regulated NTE expression and GPC content in mammalian cells.

The results of this work were recently published in Pharmacolgical Research. See “Chen JX, Long DX, Hou WY, Li W, Wu YJ*. (2010) Regulation of neuropathy target esterase by the cAMP/protein kinase A signal. Pharmacolgical Research, 62, 259-264.” (*corresponding author). This work was supported by the grants from National Natural Science Foundation of China (No.30870537).