G protein coupled receptors (GPCRs) are by far the largest family of signaling receptors, and are the darlings of the pharmaceutical industry. Normal receptor signaling depends on accurate trafficking of signaling receptors to specific locations in the cell. Despite this obvious significance, we still know relatively little about the protein machineries that mediate trafficking of signaling receptors, the regulatory events that control these protein machineries, and the functional consequences of these regulatory events to receptor signaling. Research in the lab addresses fundamental questions in these areas using GPCRs important in drug addiction as model signaling receptors.
Specific projects:
Regulation of endocytosis of opioid receptors by addictive drugs
Activated signaling receptors are removed from the surface via endocytosis through clathrin-coated pits. In contrast to the long-standing idea that receptors are passive ‘cargo’ in the endocytic pathway, our recent data suggest that some GPCRs actively control their own fate by specifically regulating the kinetics of subsets of clathrin-coated pits. We are investigating the mechanisms by which opioid receptors, the targets of many clinically abused drugs, regulate endocytic kinetics. These mechanisms suggest a novel mode of opioid regulation that likely plays a key role in drug addiction.
Sorting of signaling receptors in the endosome.
Endocytosed GPCRs may be recycled to the cell surface, thus allowing the cell to respond to the signal again, or may be targeted to the lysosome to be destroyed, leading to prolonged ‘de-sensitization’ of the cell. Despite this clear significance to signaling, how different receptors are sorted into distinct trafficking pathways in the endosome is not known. We have identified a novel role for an actin-based machinery in selectively directing specific receptors to the recycling pathway, and are investigating the biochemical mechanisms, regulation by homologous and heterologous signaling pathways, and functional relevance of this machinery in opioid and adrenergic signaling.
Regulated surface insertion of receptors from the biosynthetic pathway.
In the case of GPCRs that are sorted into the lysosome and destroyed, the cell is re-sensitized only when newly synthesized GPCRs are inserted on the plasma membrane from the biosynthetic pathway. While there is evidence that biosynthetic insertion of receptors is highly regulated in neurons, we know very little about the signaling mechanisms that regulate this insertion and their functional significance. We use the delta-opioid receptor, whose biosynthetic trafficking is regulated, as a model receptor to study the general principles, mechanisms, and functional consequences of regulated insertion of signaling receptors on the plasma membrane.