Neuronal nicotinic acetylcholine receptors (nAChR) are acetylcholine-gated cation channels that are widely distributed in the central and peripheral nervous systems. The nAChR is found postsynaptically at synapses, where they may mediate signal transduction between neurons. In addition, these receptors are located at presynaptic, perisynaptic and extrasynaptic sites where they may affect signal transduction processes of other neurotransmitters. The nAChRs are likely involved in neuronal development, plasticity, and other physiological roles that are just being revealed. These receptors have also been implicated in diseases such as epilepsy, Alzeimer’s disease, Parkinson’s disease and schizophrenia. The interaction of nAChRs with nicotine is the key step in the process that leads to nicotine addiction.

Each of the nAChRs is thought to be formed from five subunits. Eleven different subunit genes have been identified in vertebrate neuronal tissue, which allows for the possibility of multiple nAChR subtypes. We have expressed the different nAChR subtypes in HEK 293 cells. The stable clonal cell lines generated from the heterologous expression provide cell models for each of the nAChR subtypes. We are using these cell lines to study the molecular biological, pharmacological, functional and pathological characteristics of nAChR subtypes.

Selected Publications:

• Levin ED, Rezvani AH, Xiao Y, Slade S, Cauley M, Wells C, Hampton D, Petro A, Rose JE, Brown ML, Paige MA, McDowell BE, Kellar KJ: Sazetidine-A, a Selective {alpha}4{beta}2 Nicotinic Receptor Desensitizing Agent and Partial Agonist, Reduces Nicotine Self-Administration in Rats. J Pharmacol Exp Ther. [Epub ahead of print]

• Hone AJ, Whiteaker P, Christensen S, Xiao Y, Meyer EL, McIntosh JM: A novel fluorescent alpha-conotoxin for the study of alpha7 nicotinic acetylcholine receptors. J Neurochem. 111:80-9, 2009

• Xiao Y, Abdrakhmanova GR, Baydyuk M, Hernandez S, Kellar KJ: Rat neuronal nicotinic acetylcholine receptors containing alpha7 subunit: pharmacological properties of ligand binding and function. Acta Pharmacol Sin. 30:842-50, 2009

• Valette H, Xiao Y, Peyronneau MA, Damont A, Kozikowski AP, Wei ZL, Kassiou M, Kellar KJ, Dollé F, Bottlaender M: 18F-ZW-104: a new radioligand for imaging neuronal nicotinic acetylcholine receptors--in vitro binding properties and PET studies in baboons. J Nucl Med. 50:1349-55, 2009

• Gao Y, Ravert HT, Kuwabara H, Xiao Y, Endres CJ, Hilton J, Holt DP, Kumar A, Alexander M, Wong DF, Dannals RF, Horti AG: Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of alpha4beta2 nicotinic acetylcholine receptors (alpha4beta2-nAChRs) in the brain with positron emission tomography. Bioorg Med Chem. 17:4367-77, 2009

• Cucchiaro G, Xiao Y, Gonzalez-Sulser A, Kellar KJ: Analgesic effects of Sazetidine-A, a new nicotinic cholinergic drug. Anesthesiology. 109:512-9, 2008

• Gao Y, Kuwabara H, Spivak CE, Xiao Y, Kellar K, Ravert HT, Kumar A, Alexander M, Hilton J, Wong DF, Dannals RF, Horti AG: Discovery of (-)-7-methyl-2-exo-[3'-(6-[18F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (alpha4beta2-nAChR) with optimal positron emission tomography imaging properties. J Med Chem. 51:4751-64, 2008

• Chen J, Higby R, Tian D, Tan D, Johnson MD, Xiao Y, Kellar KJ, Feng S, Shields PG: Toxicological analysis of low-nicotine and nicotine-free cigarettes. Toxicology. 249:194-203, 2008

• Moaddel R, Oliveira RV, Kimura T, Hyppolite P, Juhaszova M, Xiao Y, Kellar KJ, Bernier M, Wainer IW: Initial synthesis and characterization of an alpha7 nicotinic receptor cellular membrane affinity chromatography column: effect of receptor subtype and cell type. Anal Chem. 80:48-54, 2008

• Kozikowski AP, Chellappan SK, Xiao Y, Bajjuri KM, Yuan H, Kellar KJ, Petukhov PA. Chemical medicine: novel 10-substituted cytisine derivatives with increased selectivity for alpha4beta2 nicotinic acetylcholine receptors. ChemMedChem. 2:1157-1161, 2007

• Chellappan SK, Xiao Y, Tueckmantel W, Kellar KJ, Kozikowski AP: Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity. J Med Chem. 49:2673-6, 2006

• Ohtani M, Oka T, Badyuk M, Xiao Y, Kellar KJ, Daly JW: Mouse beta-TC6 insulinoma cells: high expression of functional alpha3beta4 nicotinic receptors mediating membrane potential, intracellular calcium, and insulin release. Mol Pharmacol. 69:899-907, 2006

• Xiao Y, Fan H, Musachio JL, Wei ZL, Chellappan SK, Kozikowski AP, Kellar KJ: Sazetidine-A, a novel ligand that desensitizes alpha4beta2 nicotinic acetylcholine receptors without activating them. Mol Pharmacol. 70:1454-60, 2006

• Huang Y, Zhu Z, Xiao Y, Laruelle M: Epibatidine analogues as selective ligands for the alpha(x)beta2-containing subtypes of nicotinic acetylcholine receptors. Bioorg Med Chem Lett. 15:4385-8, 2005

• Marritt AM, Cox BC, Yasuda RP, McIntosh JM, Xiao Y, Wolfe BB, Kellar KJ: Nicotinic cholinergic receptors in the rat retina: simple and mixed heteromeric subtypes. Mol Pharmacol. 68:1656-68, 2005

• Wei ZL, Xiao Y, Yuan H, Baydyuk M, Petukhov PA, Musachio JL, Kellar KJ, Kozikowski AP
Novel pyridyl ring C5 substituted analogues of epibatidine and 3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine (A-84543) as highly selective agents for neuronal nicotinic acetylcholine receptors containing beta2 subunits. J Med Chem. 48:1721-4, 2005