Doug Sheffler, Ph.D.
Assistant Professor
B.S. Biology, Saint Vincent College, 1999
Ph.D. Biochemistry, Case Western Reserve University, 2006
Biosketch and Research Interests
Douglas James Sheffler, Ph.D., is a Research Assistant Professor in the Conn laboratory. He obtained his doctoral training in the laboratory of Bryan L. Roth, M.D., Ph.D. at Case Western Reserve University in Cleveland, Ohio. His graduate studies focused on the regulation of 5-hydroxytryptamine 2A (5-HT2A) receptor signaling via a novel interaction between the third intracellular (i3) loop of the 5-HT2A receptor and a member of the mitogen-activated protein kinase family, p90 Ribosomal S6 Kinase 2 (RSK2). Doug continues to pursue his interest in GPCR signal transduction and receptor-ligand interactions in the Conn laboratory, which he joined in 2005 as a post-doctoral fellow. His post-doctoral work focused on projects related to either the metabotropic glutamate receptors (mGluRs) or to the muscarinic acetylcholine receptors (mAChRs). The mGluRs are family III GPCRs, containing a large extracellular N-terminal domain where their endogenous ligand, glutamate, binds. Alternatively, the mAChRs are family I GPCRs, which bind their endogenous ligand, acetylcholine, within the transmembrane domain. Over the years, a number of compounds have been discovered that can bind to sites that are distinct from the endogenous ligand (orthosteric) binding site of GPCRs, which are termed allosteric ligands. Allosteric ligands can directly activate (allosteric agonists) or inactivate (negative allosteric modulators, NAMs) a GPCR, or can potentiate signaling of the endogenous ligand (positive allosteric modulators, PAMs). Doug’s work initially focused on examining features of ligand-induced differential signaling exhibited by a number of mGluR1a-selective PAMs and on the pharmacological characterization of a novel M1 mAChR selective antagonist. His current research focuses on the determination of the roles of individual Group II mGluRs in modulating synaptic transmission utilizing novel mGluR2 and mGluR3 allosteric ligands.
Selected Publications
Gray JA, Sheffler DJ, Bhatnagar A, Woods JA, Hufeisen SJ, Benovic JL, Roth BL. Cell-type specific effects of endocytosis inhibitors on 5-hydroxytryptamine (2A) receptor desensitization and resensitization reveal an arrestin-, GRK2-, and GRK5-independent mode of regulation in human embryonic kidney 293 cells. Mol Pharmacol 2001 Nov; 60(5):1020-3030.
Bhatnagar A, Sheffler DJ, Kroeze WK, Compton-Toth B, Roth BL. Caveolin-1 interacts with 5-HT2A serotonin receptors and profoundly modulates the signaling of selected Gaq-coupled GPCRs. J Biol Chem. 2004 Aug 13; 279(33):34614-23.
Yan F, Mosier PD, Westkaemper RB, Stewart J, Zjawiony JK, Vortherms TA, Sheffler DJ, Roth BL. Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to kappa-opioid receptors. Biochemistry. 2005 Jun 21; 44(24):8643-51.
Davies MA, Setola V, Strachan RT, Sheffler DJ, Salay E, Hufeisen SJ, Roth BL. Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics J. 2006 Jan-Feb;6(1):42-51.
Sheffler, DJ, Kroeze, WK, Garcia, BG, Deutch, AY, Hufeisen, SJ, Leahy, P, Brüning, JC, Roth, BL. p90 Ribosomal S6 Kinase 2 Exerts a Tonic Brake on G Protein-Coupled Receptor Signaling. Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4717-22. PMCID: PMC1450237
Lewis LM, Sheffler D*, Williams R, Bridges TM, Kennedy JP, Brogan JT, Mulder MJ, Williams L, Nalywajko NT, Niswender CM, Weaver CD, Conn PJ, Lindsley CW. Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists. Bioorg Med Chem Lett. 2008 Feb 1;18(3):885-90. PMCID: PMC2275053
Sheffler DJ, Conn PJ. Allosteric potentiators of metabotropic glutamate receptor subtype 1a differentially modulate independent signaling pathways in baby hamster kidney cells. Neuropharmacology. 2008 Sep;55(4):419-27. PMCID: PMC2600811
Strachan RT, Sheffler DJ, Willard B, Kinter M, Kiselar JG, Roth BL. Ribosomal S6 kinase 2 directly phosphorylates the 5-hydroxytryptamine 2A (5-HT2A) serotonin receptor, thereby modulating 5-HT2A signaling. J Biol Chem. 2009 Feb 27;284(9):5557-73. PMCID: PMC2645816
Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN, Watson NL, Xiang Z, Zhang Y, Jones PJ, Lindsley CW, Olive MF, Conn PJ. mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning. Neuropsychopharmacology. 2009 Aug;34(9):2057-71. PMCID: In Progress
Sheffler DJ, Williams R, Bridges TM, Xiang Z, Kane AS, Byun NE, Jadhav S, Mock MM, Zheng F, Lewis LM, Jones CK, Niswender CM, Weaver CD, Lindsley CW, Conn PJ. A Novel Selective Muscarinic Acetylcholine Receptor Subtype 1 (M1 mAChR) Antagonist Reduces Seizures Without Impairing Hippocampal-Dependent Learning. Mol Pharmacol. 2009 Aug;76(2):356-68. PMCID: PMC2713127
Weaver CD, Sheffler DJ, Lewis LM, Bridges TM, Williams R, Nalywajko T, Kennedy JP, Mulder MM, Jadhav S, Aldrich LA, Jones CK, Marlo JE, Xiang Z, Niswender CM, Mock MM, Zheng F, Conn PJ, Lindsley CW. Discovery and Development of a Potent and Highly Selective Small Molecule Muscarinic Acetylcholine Receptor Subtype I (mAChR 1 or M(1)) Antagonist In vitro and In vivo Probe. Curr Top Med Chem. 2009;9(13):1217-26. PMCID: In Progress
Strachan RT, Allen JA, Sheffler DJ, Roth BL. p90 Ribosomal S6 kinase 2, a novel GPCR kinase, is required for growth factor-mediated attenuation of GPCR signaling. Biochemistry. 2010 Mar 30;49(12):2657-71. PMCID: In Progress
Jin X, Semenova S, Yang L, Ardecky R, Sheffler DJ, Dahl R, Conn PJ, Cosford NDP, Markou A. The mGluR2 Positive Allosteric Modulator BINA Decreases Cocaine Self-Administration and Cue-Induced Cocaine-Seeking and Counteracts Cocaine-Induced Enhancement of Brain Reward Function in Rats. Neuropsychopharmacology. Neuropsychopharmacology. 2010 Sep;35(10):2021-36. PMCID: In Progress
*Denotes co-first or co-corresponding authors
