What we've done
Cells sense and react to their environment by changing the composition of plasma membrane proteins. Cell surface remodeling is essential for regulating the cells' interaction with the extracellular milieu. Learning how membrane-proteins are identified and eliminated is crucial for understanding cell and organismal homeostasis.
Our work uncovers a novel high-affinity receptor for cocaine and explores the role of autophagic proteostasis in drug abuse and SARS-CoV-2 entry into cells.
We found that sub-nanomolar levels of cocaine induce autophagy in neurons. This effect on autophagy is three orders of magnitude more potent than cocaine-mediated inhibition of the dopamine transporter (DAT) activity. Our research shows that autophagic degradation of DAT primarily mediates the stimulant effect of cocaine (link to the paper). Using CRISPR/Cas9 generated mutant mice, we are interrogating the role of autophagy in the selective targeting of membrane proteins to regulate cell signaling, modulate behavior, and mediate neurotoxicity.
We identified the brain acid-soluble protein-1 (BASP1) as a novel high-affinity receptor for cocaine (Kd 7 nM) (link to the paper). Using BASP1 conditional knockout mice, the Harraz lab currently characterize BASP1 as a candidate receptor for cocaine.