G-protein coupled receptors constitute the single largest family of cell surface receptors that mediate physiological responses to a wide variety of stimuli. These receptors are characterized by seven transmembrane domains (see figure 1); they interact with heterotrimeric G-proteins to transduce cellular signals. For a number of years we have focused our studies on understanding the molecular mechanisms that modulate opioid receptors; these receptors are activated by binding to classic opiates such as morphine. Recently we discovered that receptor dimerization is a novel mechanism that modulates opioid receptor function. Specifically, opioid receptors heterodimerize with other members of the G-protein coupled receptor family, which leads to changes in agonist affinity, potency, and receptor trafficking. The elucidation of the molecular mechanisms involved in modulating receptor function is a compelling strategy for identifying appropriate compounds to treat narcotic addiction.

The second research project is directed towards understanding the regulation of neuroendocrine peptide biosynthesis. A wide variety of proteins in neural, endocrine and immune tissues undergo proteolytic processing. Many of these proteins and peptides are intercellular messengers. 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. One area of interest is the regulation of endopeptidases and exopeptidases involved in the biosynthesis of neuroendocrine peptides. Using transgenic animals lacking processing enzymes we have characterized the contribution of various enzymes to the generation of dynorphin peptides. Recently, we have isolated and identified novel neuropeptides from the brains of these transgenic animals. Studies to characterize the function of these peptides and their receptors are the currently underway.