Dr. John Mihic
Office: MBB 1.148
phone: (512) 232-7174
email:
John Mihic received his Ph.D. in Pharmacology from the University of Toronto in 1992. He did his postdoctoral work in the Department of Pharmacology at the University of Colorado Health Sciences Center, becoming an Instructor in that department in 1995. In 1997 he moved to the Department of Physiology & Pharmacology at the Wake Forest University School of Medicine, where he contributed to the formation of an NIH-funded Alcohol Research Center. In 1999 he won the 12th annual Young Investigators Award from the Research Society on Alcoholism. Dr. Mihic moved his lab to the University of Texas at Austin in May, 2000 where he is currently an associate professor in the Section of Neurobiology as well as a member of the Waggoner Center for Alcohol & Addiction Research and the Institutes for Neuroscience and Cellular & Molecular Biology. He is currently serving a four-year term on the ALTX-3 NIH study section.
Research Interests
The rational development of therapies for alcohol and drug abuse requires an understanding, on a molecular level, of how these drugs affect the operation of ion channels in the brain. At present, the molecular targets in the brain responsible for the acute effects of alcohol and inhaled drugs of abuse are not well understood. We also do not understand the molecular mechanisms that underlie drug tolerance and dependence.
Research in my laboratory is focused on characterizing the molecular mechanisms through which alcohol, inhaled solvents, sedatives and anaesthetics act on ligand-activated ion channels. Our studies focus on the GABA-A and glycine receptors, since GABA and glycine are the major inhibitory transmitters in the brain. We also study serotonin-3 receptors, since serotonin is a major neuromodulator in the brain. We combine the techniques of chimeragenesis and mutagenesis to produce channels constructed from amino acids whose sequences are slightly altered due to the mutations we introduced. We then evaluate the physiological changes that result from the structural modifications we induced. We do this by injecting the mRNA that codes for the mutated channels into cultured cells or Xenopus oocytes, which then express the mutated channels. The newly expressed channels are studied electrophysiologically to determine which channels properties were changed by the modifications we introduced.
These studies have thus far identified specific amino acids of these receptors responsible for enhancement of the inhibition produced by GABA-A and glycine receptors when they bind alcohol or inhaled solvents. Current work in the lab is continuing to characterize alcohol and anaesthetic actions on these receptors and we are also attempting to discover sites of action of these drugs on the serotonin-3 receptor. Our long-term goals include the creation of knock-in mice bearing these mutated receptors; these animals will greatly increase our understanding of the relevance of each receptor for the known actions of alcohol, inhalants and sedatives in animals, including ourselves. Other research interests in the lab include the elucidation of the basic mechanisms of ion channel opening and receptor desensitization that occurs after neurotransmitter binding, as well as studies on the molecular mechanisms that regulate the assembly of the subunits from which ion channels are built.