Keywords: Dopamine receptors/transporters/glutamate receptors/nicotinic receptors/ protein-protein interactions
It has become more evident that many pathological states in the CNS do not result exclusively from single gene dysfunctions. Recently, we have shown an elaborate cross-talk of neurotransmitter receptors suggesting that the pathophysiology of neuronal disorders may involve modifications to more than just one neurotransmitter systems. I am particularly interested in understanding the molecular interactions among various neurotransmitter receptors/ transporters/ligand-gated ion-channels that may contribute to unlocking the mysteries of the neuronal brain dysfunctions, such as drug addiction, major depression, schizophrenia, Parkinson’s disease, multiple sclerosis and stroke. In 2000, our team provided the first molecular evidence that direct protein-protein interaction enables functional cross-talk between G protein-coupled receptors and ligand-gated ion channels (Liu et al., 2000 Nature). We have now extended our investigation to several other receptors (Lee et al., 2002, Cell; Pei et al., 2004; Zou et al., 2005 Journal of Neuroscience; Pei et al., 2010 Nature Medicine) and furthermore, we identified that altered protein-protein interactions might provide the molecular basis of human diseases. As an example, we discovered that decreased protein-protein interaction between dopamine transporters and D2 receptors could play a critical role in the pathology of schizophrenia (Lee et al., 2007 EMBO Journal; Lee et al., 2009 Synapse). Most importantly, we also developed several small protein peptides that are able to interfere with specific protein-protein interactions and thereby exert a “therapeutic” effect in in vivo animal models-- an example being an interfering protein peptide that shows efficacy in animal models of depression (Pei et al., 2010 Nature Medicine) and nicotine addiction respectively (Li et al., 2012 Journal of Experimental Medicine).
Cell and tissue culture: Brain slice, hippocampal cells, neurons.
Procedures: Adenovirus, behavioural tests, immunohistochemistry, immunocytochemistry, mass spectrometry, proteomics, signal transduction characterization, siRNA, stereotaxic brain surgery, western blot.