Biochemistry; Neurobiology; Neurochemistry; Neuropharmacology
Membrane Proteins - Pumps and Transporters
Neurobiology and Physiology of Synapses
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.
- 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. J Biol Chem. 2012 Aug 31. [Epub ahead of print]
- 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. J. Biol. Chem. 2012;287(22):18524-34
- Tavoulari S., Rizwan, A.N., Forrest, L.R. and Rudnick G. Reconstructing a chloride binding site in a bacterial neurotransmitter transporter homologue. (2011) J Biol Chem 286: 2834-2842.
- Zhang, Y-W and Rudnick, G. Myristoylation of cGMP-dependent protein kinase dictates isoform specificity for serotonin transporter regulation. (2011) J Biol Chem 286: 2461-2468.
- Tao Z, Zhang YW, Agyiri A, Rudnick G. Ligand effects on cross-linking support a conformational mechanism for serotonin transport. JBC. 2009;284(49):33807-14.
- Tavoulari S, Forrest LR, Rudnick G. Fluoxetine (Prozac) binding to serotonin transporter is modulated by chloride and conformational changes. J Neurosci. 2009 Jul 29;29(30):9635-43.
- Forrest LR, Zhang YW, Jacobs MT, Gesmonde J, Xie L, Honig BH, Rudnick G. Mechanism for alternating access in neurotransmitter transporters. Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10338-43