Analysis of the proteome of organic cation transporters: relevance for function and regulation

Basic data for this project

Description

Polyspecific organic cation transporters (OCT) play an important role in tissue distribution of endogenous and exogenous organic cations and in their renal and hepatic secretion. We could show that the membrane expression and function of OCT are regulated by direct interaction with lysosome-associated protein trans membrane 4α (LAPTM4α) and with tetraspanin CD63, which results in recruitment of OCT to an endocytotic or a transcytotic pathway, respectively. Moreover, we also showed that OCT form oligomers, which are important for cellular processing and membrane insertion of the transporter. Now, we plan to identify the interaction domains responsible for the OCT interaction with LAPTM4α and CD63 and to study the role of OCT interaction with CD9 and Dyrk1A, which we also identified as partners. Moreover, the in vivo role of the OCT-CD63 interaction will be investigated in isolated proximal tubules of CD63 knockout mice. Finally, we will attempt to modulate the expression of these interaction partners using new in vivo gene silencing techniques in the mouse kidney. The interaction of OCT with monoamine neurotransmitters and drugs and their importance for cellular accumulation of toxic substances makes the identification of OCT interaction partners highly interesting under physiological, pathological, and also pharmacological aspects and offers new possible therapeutic approaches.