Senior Scientist, Vollum Institute
After earning his Ph.D. in Pharmacology from Loyola University in 1979, John Williams worked as a research scientist at the Max-Planck Institute in Munich and at Loyola University School of Medicine. He then spent five years as a research scientist in Biological Sciences at the Massachusetts Institute of Technology. In 1987, he became an assistant staff scientist at the Vollum Institute and rose to the position of senior scientist in 1996. He holds a concurrent appointment in the Department of Physiology and Pharmacology in the School of Medicine. Williams earned his B.S. from St. Lawrence University and his M.S. from the State University of New York at Potsdam.
Summary of current research
John Williams and colleagues investigate the early events that lead to the development of tolerance to opioids. Opioids such as morphine are important therapeutic compounds used for the management of pain. The primary problem with the use of opioids is the development of tolerance, where higher doses of morphine are required to achieve the same effect. One ongoing project is the study of opioid actions on neurons in the locus coeruleus. Opioids bind to mu opioid receptors found on locus coeruleus neurons and result in the activation of an inwardly rectifying potassium conductance. Recent work has shown that even a brief treatment with a potent opioid agonist results in a transient decrease in the ability to activate the receptor (desensitization). This desensitization is thought to be one of the earliest steps leading to the long-term decrease in receptor sensitivity found with long-term morphine treatment. A current project focuses on the mechanisms that underlie this desensitization and its reversal.
Another brain area under study is the ventral tegmental area (VTA). This region contains dopamine cells that are an important component of the endogenous reward pathway in the brain. Many abused drugs (cocaine, amphetamine, opioids, nicotine) act in this area to increase the release or presence of dopamine in the extracellular space. Both psychostimulants and opioids cause a presynaptic inhibition of GABA inhibitory postsynaptic potentials in dopamine cells, thus increasing their excitability and causing the release of dopamine. Although glutamate is best known as an excitatory transmitter, it also causes slow inhibitory postsynaptic potentials (IPSPs) in dopamine cells through activation of a metabotropic glutamate receptor. Psychostimulants block the IPSP mediated by glutamate, while leaving the excitatory postsynaptic potential in place. Thus, psychostimulants can increase dopamine release in the brain by several different mechanisms.
Recent studies have focused on the release of dopamine from within the VTA. The regulation of dopamine release is one of the cornerstones in the understanding of the endogenous reward pathway. Studies have focused on the identification of an IPSP mediated by dopamine in this area. This synaptic potential is the first of its kind and offers the opportunity to study the basic mechanisms that control dopamine release as well as the direct actions of drugs of abuse on this key transmitter. One observation resulting from this work is the realization that the pool of dopamine used for synaptic transmission is very labile. Dopamine release can be increased or decreased rapidly after treatment with a variety of drugs. Among the drugs that increase dopamine release is L-DOPA, an agent used commonly for patients with Parkinson's disease. The mechanisms that regulate synaptic release of dopamine may help explain the actions of certain therapeutic drugs as well as the long-term effects of drugs of abuse.
Lebowitz JJ, Banerjee A, Qiao C, Bunzow JR, Williams JT, Kaeser PS. (2023) Synaptotagmin-1 is a Ca2+ sensor for somatodendritic dopamine release. Cell Reports. 42(1),111915.
Adhikary S, KoitaO, Lebowitz JJ, Birdsong WT, Williams JT (2022) Agonist-Specific Regulation of G Protein–Coupled Receptors after Chronic Opioid Treatment. Molecular pharmacology. 101(5),300-308.
Condon AF, Assad N, Dore TM, Williams JT (2022) Co-activation of GPCRs facilitate GIRK-dependent current. Journal of Physiology. 600(22),4881-4895.
Lebowitz JJ, Trinkle M, Bunzow JR, Balcita-Pedicino JJ, Hetelekides S, Robinson B, De La Torre S, Aicher SA, Sesack SR, Williams JT (2022) Subcellular localization of D2 receptors in the murine substantia nigra. Brain structure Function. 227,925–941.
Condon AF, Robinson BG, Asad N, Dore TM, Tian L, Williams JT (2021) The residence of synaptically released dopamine on D2 autoreceptors. Cell Reports 36(5):109465.
Birdsong WT, Williams JT (2020) Recent Progress in Opioid Research from an Electrophysiological Perspective. Molecular Pharmacology. 98(4),401-409.
Leff ER, Arttamangkul S, Williams JT. (2020) Chronic treatment with morphine disrupts acute kinase-dependent desensitization of GPCRs. Mol. Pharmacol. 98:497-507.
Asad N, McLain DE, Condon AF, Gore S, Hampton SE, Vijay S, Williams JT, Dore TM (2020) Photoactivatable Dopamine and Sulpiride to Explore the Function of Dopaminergic Neurons and Circuits. ACS Chem Neurosci. 11(6),939-951.
Arttamangkul S, Plazek A, Platt EJ, Jin H, Murray TF, Birdsong W, Rice KC, Farrens D, Williams JT (2019) Visualizing endogenous opioid receptors in living neurons using ligand-directed chemistry. Elife 8:e49319.
Robinson BG, Cai X, Wang J, Bunzow JR, Williams JT, Kaeser PS. (2019) RIM is essential for stimulated but not spontaneous somatodendritic dopamine release in the midbrain. Elife 8:e47972.
Arttamangkul S, Leff ER, Koita O, Birdsong WT, Williams JT. (2019) Separation of acute desensitization and long-term tolerance of µ-opioid receptors is determined by the degree of C-terminal phosphorylation. Mol. Pharmacol. 96:505-514.
Arttamangkul S, Heinz DA, Bunzow JR, Song X, Williams JT. (2018) Cellular tolerance at the mu-opioid receptor is phosphorylation dependent. Elife 7. pii:e34989.
Levitt ES, Williams JT. (2018) Desensitization and tolerance of mu opioid receptors on pontine Kölliker-Fuse neurons. Mol. Pharmacol. 93:8-13.
Gantz SC, Levitt ES, Llamosas N, Neve KA, Williams JT. (2015) Depression of serotonin synaptic transmission by the dopamine precursor L-DOPA. Cell Reports 12:944-954.
Banghart MR, Williams JT, Shah RC, Lavis LD, Sabatini BL. (2013) Caged naloxone reveals opioid signaling deactivation dynamics. Mol. Pharmacol. 84:687-695.
Gantz SC, Bunzow JR, Williams JT. (2013) Spontaneous inhibitory synaptic current mediated by a G protein-coupled receptor. Neuron 78:807-812.
Ford CP, Phillips PE, Williams JT. (2009) The time course of dopamine transmission in the ventral tegmental area. J. Neurosci. 29:13344-13352.
Virk MS, Williams JT. (2008) Agonist-specific regulation of mu-opioid receptor desensitization and recovery from desensitization. Mol. Pharmacol. 73:1301-1308.
Beckstead MJ, Grandy DK, Wickman K, Williams JT. (2004) Vesicular dopamine release elicits an inhibitory postsynaptic current in midbrain dopamine neurons. Neuron 42:939-946.
Morikawa H, Khodakhah K, Williams JT. (2003) Two intracellular pathways mediate metabotropic glutamate receptor-induced Ca2+ mobilization in dopamine neurons. J. Neurosci. 23:149-157.
Fiorillo CD, Williams JT. (1998) Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature 394:78-82.
Harris GC, Williams JT. (1991) Transient homologous mu-opioid receptor desensitization in rat locus coeruleus neurons. J. Neurosci. 11:2574-2581.
Williams JT, Egan TM, North RA. (1982) Enkephalin opens potassium channels in mammalian central neurones. Nature 299:74-77.