Dr. Palmer Taylor: Molecular Recognition in the Cholinergic Nervous System

Research Summary: Neuropharmacology Synapses and Receptor Mechanisms

Dr. Taylor’s research is directed to structure, recognition capacity, and regulation of expression of proteins governing neurotransmission in cholinergic synapses. His group cloned the first acetylcho-linesterase (AChE) gene 25 years ago. This was followed by analysis of its genomic DNA to delineate regulatory regions, multiple splicing options and gene expression profiles in nerve and muscle. His studies of AChE structure and its complexes by crystallography and fluorescence spectroscopy, characterizing a peripheral site on AChE and demonstrating flexibility of the active center gorge, provided the basis for studies with Barry Sharpless’ group at the Scripps Research Institute employing freeze-frame, click-chemistry. The very biological target, AChE, is used as the template in the synthesis of high affinity, selective inhibitors. Dr. Taylor’s longstanding work with nicotinic acetylcholine receptors (nAChR) defined ligand specificity in relation to state functions for receptor activation and desensitization and identified structural determinants on nAChR governing ligand and peptide toxin specificity. More recently, he examined the acetylcholine binding protein, a soluble surrogate of the receptor. His group, in collaboration, employed physical methods of fluorescence anisotropy decay, NMR, x-ray crystallography and deuterium-hydrogen exchange to examine structure and selectivity of ligand binding sites. Finally, Dr. Taylor’s group uncovered much of what is known about the structure of neuroligin, a synaptic adhesion molecule homologous to AChE and its partner neurexin. Their structural studies have delineated alterations in processing and folding associated with congenital mutations found in the autism spectrum disorders. These pathways suggest potential therapeutic modalities for this developmental condition.

Academic Achievements

Education: B.S and Ph.D. in Physical Pharmacy University of Wisconsin; Post-doctoral fellow NIH and Cambridge University, UK.

Leadership Experience: Chair, Dept. of Pharmacology UCSD (1987-2003); Dean, Skaggs School of Pharmacy & Pharm. Sci. (2002 – present); President, Amer. Soc. for Pharmacology. & Exp. Therapeutics (1995); NIH National Advisory Councils NIGMS, (1988-1992); NIEHS (2009-present).

Teaching

• Lectures and course directorships in pharmacology and toxicology to medical, pharmacy and Ph.D. students.
• CCo-editor and co-author: Goodman & Gilman’s, Pharmacological Basis of Therapeutics; Principles of Drug Action.

Key Contributions to Pharmaceutical Sciences

• Sequenced AChE, cloned its cDNAs and gDNA and described structure-function relationships for AChE inhibitors and novel reactivators.
• Determined the molecular basis for occupation, ligand selectivity, and response efficacy of nicotinic acetylcholine receptors and through AChBP.
• Analyzed the structural basis of neuroligin-neurexin function in synapses.

Selected Recent Publications (from 240 peer-reviewed articles)

Hibbs et al (2009). Structural determinants for inter-action of partial agonists with acetylcholine binding protein and neuronal α7 nicotinic acetylcholine receptor. EMBO Journal 28:3040-3051.

De Jaco et al (2010). Neuroligin trafficking deficiencies arising from mutations in the alpha/beta-hydrolase fold protein family J Biol Chem., 285:28674-28682.

Miller, M.T., et al (2011). The crystal structure of the α-neurexin-1 extracellular region reveals a hinge point for mediating synaptic adhesion and function. Structure, 19, 767-778 Cover Article

Radic, Z., et al (2012). Refinement of structural leads for centrally acting oxime reactivators of phosphylated cholinesterases. J. Biol. Chem. 287. 11798-11809

Potential Collaborative Programs with the Pharmaceutical Industry:

Drug discovery for Cys loop receptor targets. Therapy for protein stabilization in congenital autism spectral disorders.