1.  Opioid receptor dimerization, pharmacology, and signaling

2.  Neuroendocrine peptide biosynthesis and processing

3.  Neuroproteomics of the synapse and opiate addiction

One of the research projects in the Devi Laboratory is focused on exploring the molecular mechanisms and the functional implications of opioid receptor dimerization. Opioid receptors are G protein-coupled receptors that are activated by opiate drugs such as morphine and heroin. Recently, we discovered that opioid receptors associate with each other and with other members of the G protein-coupled receptor family. This leads to changes in the pharmacological and signaling properties of the receptors, including ligand affinity, potency, and receptor trafficking. Thus, receptor-receptor interactions represent a novel mechanism for modulating opioid receptor function. We are currently investigating the physiological relevance of dimerization, as well as screening for drugs that target receptor heterodimers. Another research project is directed toward understanding the regulation of neuroendocrine peptide biosynthesis. Most neuroendocrine peptides, including opioid peptides, are synthesized from precursor proteins. Post-translational processing of these precursors is a key step in the production of biologically active peptides. We are studying the regulation of endopeptidases and exopeptidases involved in the biosynthesis of neuroendocrine peptides. In addition, using transgenic animals lacking processing enzymes, we are isolating and identifying novel neuropeptides. Studies to characterize the function of these peptides and their receptors are currently underway. The most recent project in the laboratory involves the use of cutting-edge neuroproteomic and neuropeptidomic techniques to study opiate addiction. Although chronic opiate use is known to produce long-lasting neural adaptations, the mechanisms underlying these changes are not well understood. We are using modern proteomic techniques (such as two-dimensional gel electrophoresis, differential isotopic labeling, and MS/MS sequencing) to analyze morphine-induced changes in the levels of synaptic proteins and neuropeptides. This approach will serve as a starting point to elucidating the molecular mechanisms underlying opiate addiction, as proteins/peptides that are altered by morphine treatment are likely to be involved in opiate-induced plasticity.