Superfund Research Program | Research Projects

Project 6

Cholinesterase Inhibition as a Target of Pesticide Residues and the Effect of Cholinergic Intervention on Gene Expression

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Dr. Palmer Taylor

Cholinesterase inhibitors account for more than half the poisonings in California from home garden and agricultural use. Therefore, the widespread use of these agents in agriculture presents a major toxicity problem, typically from soil runoff following a rain storm. As a means of detecting cholinesterase inhibitors, this project is developing technologies using high titer antibodies and mass spectrometry to detect phosphorylated and unphosphorylated acetylcholinesterase. The symptoms and target of acute toxicity from cholinesterase inhibitors are well known, but the sites and precise mechanisms of chronic toxicity remain an enigma. Therefore, to correlate residual inhibition with long-term toxicity, investigators have developed cholinesterase inhibitors selective for the central and peripheral nervous systems. Variations in gene expression that arise from localized cholinesterase inhibition in the brain and periphery are being examined. Inhibition by these agents can be expected to result in overstimulation of cholinergic pathways leading to more prolonged alterations in gene expression. Microarray chips are being used to detect changes in localized gene expression in regional brain areas and periphery following exposure to the insecticides. Gene trap methods will identify exposure-sensitive genes in culture. Candidate genes, including some known to be responsible to cholinergic stimulation are the early immediate genes (c-jun and c-fos), several regulatory kinases (JNK, p38, and IKK), and various transcriptional factors (NF-kB, Egr-1, Egr-3, and the Wilms tumor gene). This project will also examine cholinesterase inhibitors in animals in which the responsive gene has been eliminated.

Main Contact info

Dr. Palmer Taylor, Project Leader
University of California, San Diego
Department of Pharmacology
9500 Gilman Drive
BSB 3044, M/C: 0636
La Jolla, CA 92093-0636
P: 858-534-1366
F: 858-534-8248
E-mail:

News & Announcements

UCSD SBRP scientist co-discovers how particular genetic mutations affect autism spectrum disorder
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Recent Publications and Documents

Miller, M.T., Mileni, M., Comoletti, D., Stevens, R.C., Harel, M., Taylor, P. (2011) The Crystal structure of the alpha-neurexin-1 extracellular region reveals a hinge point for mediating synaptic adhesion and function. Structure 19(6):767-78, 2011. PMC Pending
PubMed ID: 21620717

Leone, P., Comoletti, D., Taylor, P., Bourne, Y., and Marchot, P. (2010). Structure-function relationships of the alpha beta-hydrolase fold domain of neuroligin: A comparison with acetylcholinesterase. Chem-Biol. Interact., 187: 49-55 PMC Pending
PubMed ID: 20100470

De Jaco, A., Lin, M.Z., Dubi, N., Comoletti, D., Miller, M.T., Camp, S., Ellisman, M., Butko, M.T., Tsein, R.Y., Taylor, P, (2010) Neuroligin Trafficking Deficiencies Arising from Mutations in the alpha/beta-Hydrolase Fold Protein Family. J Biol Chem 285, 37 :28674-28682 PMC2937894
PubMed ID: 20615874

Leone, P., Comoletti, D., Ferracci, G., Conrod, D., Garcia, S., Taylor, P., Bourne, Y., and Marchot, P. (2010) Structural insights into the exquisite selectivity of neurexin/neuroligin synaptic interactions. EMBO Journal, 29:2461-2471. PMC2910273
PubMed ID: 20543817

Wang, X., Lee, J., Di Jeso, B., Treglia, A.S., Comoletti, D., Dubi, N., Taylor, Plk and Arvan, P. (2010) Cis and trans actions of the cholinesterase-like domain within the thyroglobulin dimer. J Biol Chem 285, 23:17564-17573. PMC2878521
PubMed ID: 20353937

Comoletti, D., Miller, M., Jeffries, C.M., Wilson, J., Demeler, B., Taylor, P., Trewhella, J., and Nakagawa, T. (2010) The macromolecular architecture of the extracellular domain of alpha-NRXN1: domain organization, flexibility, and insights into trans-synaptic disposition. Structure 18, 1044-1053 PMC2948785
PubMed ID: 20696403

Camp S, Zhang L, Krejci E, Dobbertin A, Bernard V, Girard E, Duysen EG, Lockridge O, De Jaco A, Taylor P. Contributions of selective knockout studies to understanding cholinesterase disposition and function. Chem Biol Interact Epub Ahead of Print, 2010.
PubMed ID: 20153304

Boudinot E, Bernard V, Camp S, Taylor P, Champagnat J, Krejci E, Foutz AS. Influence of differential expression of acetylcholinesterase in brain and muscle on respiration. Respir Physiol Neurobiol. 165(1):40-8, 2009.
PubMed ID: 18977317

Dobbertin A, Hrabovska A, Dembele K, Camp S, Taylor P, Krejci E, Bernard V. Targeting of acetylcholinesterase in neurons in vivo: a dual processing function for the proline-rich membrane anchor subunit and the attachment domain on the catalytic subunit. J Neurosci. 29(14):4519-30, 2009.
PubMed ID: 19357277

Camp, S., De Jaco, A., Zhang, L., Marquez, M., De Lar Torre, B., and Taylor, P. Acetylcholinesterase Expression in Muscle is Specifically Controlled by a Promoter-Selective Enhancesome. J. Neuroscience 28(10):2459-2470, 2008.
PubMed ID: 18322091

Comoletti D, Grishaev A, Whitten AE, Taylor P, Trewhella J. Characterization of the solution structure of a neuroligin/beta-neurexin complex. Chem Biol Interact. Sep 25;175(1-3):150-5, 2008. PMC2587492
PubMed ID: 18550038

De Jaco A, Comoletti D, King CC, Taylor P.Trafficking of cholinesterases and neuroligins mutant proteins. An association with autism. Chem Biol Interact. Sep 25;175(1-3):349-51, 2008. PMC2692863
PubMed ID: 18555979

Comoletti D, Grishaev A, Whitten A, Tsigelny I, Taylor P, Trewhella J. Synaptic arrangement of the neuroligin/beta-neurexin complex revealed by X-ray and neutron scattering. Structure 15(6): 693-705, 2007.
PubMed ID: 17562316

Fabrichny, IP., Leone, P., Salzanbacher, G., Comoletti, D., Miller, MT., Taylor, P., Bourne, Y., and Marchot, P. Structural Analysis of the Synaptic Protein Neuroligin and its beta-Neurexin Complex: Determinants for Folding and Cell Adhesion. Neuron, 56, 979-91. (2007). PMC2703725PMC2677967
PubMed ID: 18093521

Comoletti D, Flynn RE, Boucard AA, Demeler B, Schirf V, Shi J, Jennings LL, Newlin HR, Südhof TC and Taylor P. Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins. Biochemistry 45:12816-12827, 2006.
PubMed ID: 17042500

De Jaco A, Comoletti D, Kovarik Z, Gaietta G, Radic Z, Lockridge O, Ellisman MH, Taylor, P. A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha,beta-hydrolase fold protein family. J. Biol. Chem.281(14):9667-76, 2006.
PubMed ID: 16434405

Shi J, Koeppe JR, Komives EA, Taylor P. Ligand-induced conformational changes in the acetylcholine-binding protein analyzed by hydrogen-deuterium exchange mass spectrometry. J Biol Chem. 281(17):12170-7, 2006.
PubMed ID: 16484218

Comoletti D, De Jaco A, Jennings LL, Flynn RE, Gaietta G, Tsigelny I, Ellisman MH, Taylor P. The Arg451 Cys-Neuroligin-3 Mutation Associated with Autism reveals a Defect in Protein Processing. J. Neuro 24 (20): 4889-4893, 2004.
PubMed ID: 15152050