Gary Rudnick, PhD
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Research Summary
Our research concerns the proteins involved in neurotransmitter recycling responsible for the reuptake of serotonin and other biogenic amines. We are interested in how the structure of these proteins determines their ability to couple ion gradients to substrate transport. The transporters are responsible for the process that terminates the action of serotonin, norepinephrine, and dopamine released into the synaptic cleft. They are targets for antidepressant drugs like fluoxetine (Prozac) and for stimulants such as cocaine and amphetamines, such as MDMA (ecstasy). Current efforts in the laboratory include the identification of the pathway by which serotonin passes through the membrane, including residues that are involved in substrate and inhibitor binding and those involved in conformational changes that accompany transport. We are also studying the regulation of serotonin transporter activity by phosphorylation, and we are investigating bacterial homologues of the neurotransmitter transporter family for insights into the structure of these proteins.
Extensive Research Description
We are studying the conformational changes that transport proteins undergo in moving their substrates across biological membranes.
Part of this work focuses on identifying the parts of neurotransmitter transporters (particularly serotonin transporter) that interact with substrates and ions.
We are also examining bacterial homologues of neurotransmitter transporters as model systems for understanding the mechanistic principles of transport.
Another area of research is the regulation of serotonin transport by cyclic GMP, which is defective in some individuals carrying mutant forms of the transporter and is associated with several psychiatric disorders.
Coauthors
Research Interests
Biochemistry; Neurobiology; Neurochemistry; Neuropharmacology
Research Image
The substrate binding site of LeuT
Selected Publications
- Mechanism for alternating access in neurotransmitter transporters.Forrest LR, Zhang YW, Jacobs MT, Gesmonde J, Xie L, Honig BH, Rudnick G. Mechanism for alternating access in neurotransmitter transporters. Proceedings Of The National Academy Of Sciences Of The United States Of America 2008, 105:10338-43.
- Ligand effects on cross-linking support a conformational mechanism for serotonin transport.Tao Z, Zhang YW, Agyiri A, Rudnick G. Ligand effects on cross-linking support a conformational mechanism for serotonin transport. The Journal Of Biological Chemistry 2009, 284:33807-14.
- Reconstructing a chloride-binding site in a bacterial neurotransmitter transporter homologue.Tavoulari S, Rizwan AN, Forrest LR, Rudnick G. Reconstructing a chloride-binding site in a bacterial neurotransmitter transporter homologue. The Journal Of Biological Chemistry 2011, 286:2834-42.
- Cytoplasmic permeation pathway of neurotransmitter transporters.Rudnick G. Cytoplasmic permeation pathway of neurotransmitter transporters. Biochemistry 2011, 50:7462-75.
- The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters.Bulling S, Schicker K, Zhang YW, Steinkellner T, Stockner T, Gruber CW, Boehm S, Freissmuth M, Rudnick G, Sitte HH, Sandtner W. The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. The Journal Of Biological Chemistry 2012, 287:18524-34.
- Cyclic GMP-dependent stimulation of serotonin transport does not involve direct transporter phosphorylation by cGMP-dependent protein kinase.Wong A, Zhang YW, Jeschke GR, Turk BE, Rudnick G. Cyclic GMP-dependent stimulation of serotonin transport does not involve direct transporter phosphorylation by cGMP-dependent protein kinase. The Journal Of Biological Chemistry 2012, 287:36051-8.
- How do transporters couple solute movements?Rudnick G. How do transporters couple solute movements? Molecular Membrane Biology 2013, 30:355-9.
- Two Na+ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog.Tavoulari S, Margheritis E, Nagarajan A, DeWitt DC, Zhang YW, Rosado E, Ravera S, Rhoades E, Forrest LR, Rudnick G. Two Na+ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog. The Journal Of Biological Chemistry 2016, 291:1456-71.
- Control of serotonin transporter phosphorylation by conformational state.Zhang YW, Turk BE, Rudnick G. Control of serotonin transporter phosphorylation by conformational state. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113:E2776-83.
- Structural elements required for coupling ion and substrate transport in the neurotransmitter transporter homolog LeuT.Zhang YW, Tavoulari S, Sinning S, Aleksandrova AA, Forrest LR, Rudnick G. Structural elements required for coupling ion and substrate transport in the neurotransmitter transporter homolog LeuT. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115:E8854-E8862.
- Serotonin transport in the 21st century.Rudnick G, Sandtner W. Serotonin transport in the 21st century. The Journal Of General Physiology 2019, 151:1248-1264.