Ph. D., Carnegie Mellon University
Why do we get addicted to drugs? Opioid drugs (like heroin and morphine) activate the same receptors and signaling pathways in the brain as activated by endogenous opioid peptides (like endorphins). But we rapidly develop tolerance and dependence to drugs, but far less so to endogenous opioid peptides. Why? The few clues we have point towards differences in the regulatory events that follow receptor activation as the culprit. Intracellular trafficking of opioid receptors is such a critical regulatory event that might play a role in the development of drug addiction. Despite this significance, we know very little about how trafficking of receptors regulates their signaling, and vice versa. Therefore, research in the lab uses opioid receptors and related G protein-coupled receptors (GPCRs) as examples to investigate how receptor trafficking in the brain is regulated by neuronal activity and signaling, and how they are modified in addiction.
Regulation of opioid receptor endocytosis by addictive drugs Activation of opioid and related GPCRs results in removal of activated receptors from the cell surface via endocytosis, leading to de-sensitization of the cell to the signal. The kinetics of receptor endocytosis induced by drugs are linked to their addictive potential. We have identified a novel face of endocytic regulation by opioid receptors, where receptors, instead of being passive "cargo" in endocytosis, play an active role in controlling their own destiny. We are currently investigating whether and how this active control contributes to drug addiction.
Sorting of signaling receptors in the endosome. Endocytosed receptors, including some opioid receptors, may either be returned (or recycled) to the cell surface, thus allowing the cell to respond to the signal again (i.e., be ‘re-sensitized’ to the signal), or 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 from one another in the endosome and packaged into distinct trafficking pathways is not known. We have identified a novel role for an actin-based machinery in selectively directing specific signaling receptors to the recycling pathway, and are investigating the biochemical mechanism, regulation, and functional relevance of this machinery.
Regulated surface insertion of receptors from the biosynthetic pathway. In the case of receptors that are not recycled, the cell is re-sensitized only when newly synthesized receptors are inserted on the plasma membrane from the biosynthetic pathway. Many neurons stockpile newly synthesized receptors in intracellular compartments, to deliver them to the surface in a regulated manner. The delta-opioid receptor, a clinically relevant receptor of great interest in pain management, is a classic example, as agonists targeting this receptor are not effective, arguably because there are not enough receptors on the surface. We use this receptor to study the general principles, mechanisms, and functional consequences of regulated delivery of neurotransmitter receptors, with the applied goal of developing new formulations against pain based on augmenting the biological efficacy of delta opioid receptor agonists.