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7TM receptor oligomerization and activation

Jakob Lerche Hansen

Summary

The present Ph.D. thesis contains data generated during my fellowship at the Laboratory for Molecular Cardiology, Copenhagen University Hospital during the period January 2001 to March 2004.
The 7-transmembrane (7TM) or G protein coupled receptors constitute the largest group of cell surface membrane receptors, and mediate a vast array of biological effects by activating various messengers or proteins in response to hormones, neurotransmitters and sensory stimuli. Traditionally, 7TM receptors have been considered to work as monomeric entities. However, an increasing body of evidence has shown that 7TM receptors in fact form both homo- and heterooligomers in vitro and in vivo. We have examined the calcium-sensing receptor (CaR) and the Angiotensin II type I (AT1) receptor and found, that both receptors form constitutive oligomers in living cells. Additional studies showed that AT1 receptors form oligomers during biosynthesis as early as the endoplasmatic reticulum. Coexpression of wild type AT1 and AT1 receptor mutants, defect in either ligand binding or signaling, showed that the mutant receptors specifically exerted a dominant negative effect on Gαq activation while ERK activation was preserved.
This suggests that distinct active conformations of AT1 oligomerization can couple to these respective signaling systems, and that oligomerization plays an active role in supporting these distinct active conformations of AT1 receptors. In an additional study, we have characterized three loss-of-function non-synonymous single nucleotide polymorphic AT1 receptor variants that could have important pharmacotherapeutic implications.