Faculty
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Computer color-coded autoradiograph of neuronal nicotinic receptors
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sagittal section of rat brain
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Kenneth J. Kellar
Professor of Pharmacology |
Research in my laboratory is focused on understanding the structure, function and regulation of neuronal nicotinic cholinergic receptors in the brain and the autonomic nervous system. In the brain, these receptors are strategically located where they can mediate the release of several important neurotransmitters, including dopamine, norepinephrine, acetylcholine, GABA and glutamate. In the autonomic nervous system, nicotinic receptors mediate fast excitatory transmission at ganglia; therefore, these ganglionic nicotinic receptors influence the function of nearly all peripheral organs.
Nicotinic receptors are composed of two or more protein subunits and exist as several different receptors subtypes based on their subunit composition. A major goal of our group's research is to understand how these receptor subtypes differ with regard to their specific location within the brain, their pharmacology, and their regulation. To do this, we employ a wide variety of techniques, including radioligand binding with ligands selective for subgroups of these receptors, immunoprecipitation of labeled receptors and western blot analysis of specific subunits using selective antibodies, and pharmacological characterization of receptor functions. We have used molecular biological methods to create a library of mammalian cells that stably express neuronal nicotinic receptors of defined subunit composition. These cells have allowed us to compare the pharmacological properties of these defined receptor subtypes with native neuronal receptors in CNS and ganglia.
Selected Publications:
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Hussmann GP, Yasuda RP, Wolfe BB, Xiao, Y, Kellar KJ Endogenously expressed muscarinic receptors in HEK293 cells augment up-regulation of stably expressed alpha4-beta2 nicotinic receptors. J Biol. Chem. 286:39726, 2011
- Rezvani AH, Cauley M, Sexton H, Xiao Y, Brown ML, Paige MA, McDowell BE, Kellar KJ, Levin ED. Sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague-Dawley rats. Psychopharmacology (Berl). Jan 28 2011. [Epub ahead of print]
- Lomazzo E, MacArthur L, Yasuda RP, Wolfe BB, Kellar KJ: Quantitative analysis of the heteromeric neuronal nicotinic receptors in the rat hippocampus. J Neurochem 115: 625-634, 2010
- Rezvani AH, Slade S, Wells C, Petro A, Lumeng L, Li TK, Xiao Y, Brown ML, Paige MA, McDowell BE, Rose JE, Kellar KJ, Levin ED: Effects of sazetidine-A, a selective alpha4beta2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats. Psychopharmacology (Berl). 2010
- Saba W, Valette H, Granon S, Xiao Y, Kellar KJ, Doll¨¦ F, Bottlaender M: [18F]ZW-104, a new radioligand for imaging alpha2-alpha3-alpha4/beta2 central nicotinic acetylcholine receptors: Evaluation in mutant mice. Synapse 64:570-2, 2010 No abstract available.
- 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 alpha4beta2 nicotinic receptor desensitizing agent and partial agonist, reduces nicotine self-administration in rats. J Pharmacol Exp Ther. 332:933-9, 2010
- Valette H, Xiao Y, Peyronneau MA, Damont A, Kozikowski AP, Wei ZL, Kassiou M, Kellar KJ, Doll¨¦ 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
- 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
- Cucchiaro G, Xiao Y, Gonzalez-Sulser A, Kellar KJ. Analgesic effects of Sazetidine-A, a new nicotinic cholinergic drug. Anesthesiology 109:512-519, 2008
- Cox BC, Marritt AM, Perry DC, Kellar KJ. Transport of multiple nicotinic acetylcholine receptors in the rat optic nerve: high densities of receptors containing alpha6 and beta3 subunits. J Neurochem. 105:1924-38, 2008
- Mao D, Perry DC, Yasuda RP, Wolfe BB, Kellar KJ. The alpha4beta2alpha5 nicotinic cholinergic receptor in rat brain is resistant to up-regulation by nicotine in vivo. J Neurochem. 104: 446-56, 2008
- Perry DC, Mao D, Gold AB, McIntosh JM, Pezzullo JC, Kellar KJ. Chronic nicotine differentially regulates alpha6- and beta3-containing nicotinic cholinergic receptors in rat brain. J Pharmacol. Exp. Ther. 322:306-315, 2007
- Ortinski PI, Turner JR, Barberis A, Motamedi G, Yasuda RP, Wolfe BB, Kellar KJ, Vicini S. Deletion of the GABA(A) receptor alpha1 subunit increases tonic GABA(A) receptor current: a role for GABA uptake transporters. J Neurosci. 26:9323-31, 2006
- Kellar KJ. Overcoming inhibitions. Proc Natl Acad Sci USA; 103:13263-4, 2006
- Mao D, Yasuda RP, Fan H, Wolfe BB, Kellar KJ. Heterogeneity of nicotinic cholinergic receptors in rat superior cervical and nodose Ganglia. Mol Pharmacol. 70:1693-9, 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
- Turner JR, Kellar KJ. Nicotinic cholinergic receptors in the rat cerebellum: multiple heteromeric subtypes. J Neurosci. 25:9258-65, 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