PhD defense: Joachim D. Paasche

Gamle Festsal, Urbygningen, Karl Johansgt. 47, Tuesday June 20, 2006 at 10:15.

Molecular Mechanisms of Regulation and Intracellular Trafficking of the Endothelin Receptors.

The physiological effects of the vasoactive peptide endothelin-1 (ET-1) are mediated by the ETA and ETB receptors, which belong to class A G protein-coupled receptors (GPCRs). The thesis demonstrates that ETA and ETB are internalized in a process that depend on GRK, arrestin, dynamin, and clathrin. Once internalized both the ETA and ETB receptors both enter Rab5 positive early endosomes. The two receptor subtypes are subsequently targeted to different intracellular fates. While the ETA receptor is sorted to the recycling pathway and reappears at the plasma membrane, the ETB receptor is directed to lysosomes for degradation. Analysis of carboxyl-terminally truncated ET receptors and ETA / ETB chimera revealed that that the cytoplasmic tails of the ET receptors play decisive roles in the intracellular trafficking of these receptors. Lysosomal trafficking appears to be the "default" pathway without any requirement for cytoplasmic carboxyl-terminal sorting signals. In contrast, recycling of the ETA receptor was dependent on a signal residing in the carboxyl-terminal tail of this receptor subtype. Bioinformatic and mutational analysis provide strong evidence that recycling of the ETA receptor is mediated by a motif with the structural characteristics of an internal PDZ ligand. This motif which is lacking in the carboxyl-terminal region of ETB endothelin receptors, provides a mechanism of the divergent sorting of the ETA and ETB receptor subtypes. Analysis of more than 300 G protein-coupled receptors (GPCRs) identified 35 different human GPCRs with carboxyl-terminal sequence patterns that fulfilled the structural criteria of an internal PDZ ligand. Among these were several receptors reported to follow a recycling pathway. Hence, this structural motif may represent a widely employed principle for sorting of GPCRs to the recycling pathway.











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