David R. Sibley, Ph.D.

Senior Investigator

Molecular Neuropharmacology Section

NINDS

Building 35, Room 3A201
35 Convent Drive
Bethesda, MD 20892-3723

301-496-9316

sibleyd@ninds.nih.gov

Research Topics

The long-term goal of the Molecular Neuropharmacology Section is the characterization of neurotransmitter receptor-mediated information transduction, and its regulation, across neuronal membranes. The primary model systems under investigation are those neurotransmitter receptors that are linked to their signal transduction pathways via guanine nucleotide binding regulatory (G) proteins with specific emphasis on dopamine receptor subtypes. Specific G proteins have been shown to link these receptors to the activation and inhibition of various nucleotide cyclases, phospholipases, and several ion channels. In order to characterize these receptors at the biochemical and molecular levels and study their regulation, there are several ongoing interrelated lines of research. Such projects include investigating receptor structure/function/pharmacology relationships, receptor-effector coupling mechanisms, G protein interactions, and molecular mechanisms of receptor desensitization and intracellular trafficking. We are also interested in using high throughput screening approaches to develop novel ligands for modulating dopamine receptor expression and signaling. These ligands may prove useful in the development of novel pharmacological therapies for treating numerous neurological and psychiatric disorders associated with aberrant dopaminergic signaling.

Biography

Dr. Sibley received his B.S. degree in Biology from San Diego State University and his Ph.D. in Physiology/Pharmacology from the University of California, San Diego where he worked with Ian Creese studying the ligand binding properties of dopamine receptors. He subsequently carried out postdoctoral work with Robert Lefkowitz at Duke University where he characterized adrenergic receptor regulatory mechanisms. Dr. Sibley moved to the NINDS in 1987 and was appointed Chief of the Molecular Neuropharmacology Section in 1992. His laboratory is currently investigating the molecular, cellular and biochemical properties of dopamine receptors and their role in neuronal signaling.

Selected Publications

  1. Luderman KD, Conroy JL, Free RB, Southall N, Ferrer M, Sanchez-Soto M, Moritz AE, Willette BKA, Fyfe TJ, Jain P, Titus S, Hazelwood LA, Aubé J, Lane JR, Frankowski KJ, Sibley DR. Identification of Positive Allosteric Modulators of the D<sub>1</sub> Dopamine Receptor That Act at Diverse Binding Sites. Mol Pharmacol. 2018;94(4):1197-1209.

  2. Chun LS, Vekariya RH, Free RB, Li Y, Lin DT, Su P, Liu F, Namkung Y, Laporte SA, Moritz AE, Aubé J, Frankowski KJ, Sibley DR. Structure-Activity Investigation of a G Protein-Biased Agonist Reveals Molecular Determinants for Biased Signaling of the D<sub>2</sub> Dopamine Receptor. Front Synaptic Neurosci. 2018;10:2.

  3. Kumar V, Moritz AE, Keck TM, Bonifazi A, Ellenberger MP, Sibley CD, Free RB, Shi L, Lane JR, Sibley DR, Newman AH. Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D<sub>3</sub> Receptor (D<sub>3</sub>R). J Med Chem. 2017;60(4):1478-1494.

  4. Furman CA, Roof RA, Moritz AE, Miller BN, Doyle TB, Free RB, Banala AK, Paul NM, Kumar V, Sibley CD, Newman AH, Sibley DR. Investigation of the binding and functional properties of extended length D3 dopamine receptor-selective antagonists. Eur Neuropsychopharmacol. 2015;25(9):1448-61.

  5. Conroy JL, Free RB, Sibley DR. Identification of G protein-biased agonists that fail to recruit β-arrestin or promote internalization of the D1 dopamine receptor. ACS Chem Neurosci. 2015;6(4):681-92.


This page was last updated on September 10th, 2018