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Elucidating the regulation of adenylyl cyclase type 9 by dynamic membrane trafficking

  • Author(s): Lazar, Andre Mingyuen
  • Advisor(s): von Zastrow, Mark
  • et al.
Abstract

This dissertation delves into the regulatory mechanisms that govern the dynamic redistribution of adenylyl cyclase type 9 (AC9) from the plasma membrane to the early endosome. Adenylyl cyclases (ACs) are 12-transmembrane proteins that catalyze ATP to the second messenger molecule, cyclic AMP. ACs are critical effectors of G protein activation, and AC9 is the first AC isoform described at the endosome. The introduction provides a general overview of the relationship between G protein coupled receptor (GPCR) mediated signaling and membrane trafficking. It also describes the evidence supporting GPCR-mediated signaling from the endosome, the importance of local cAMP signaling, and regulatory mechanisms that govern adenylyl cyclase isoforms. The second chapter explores the regulated endocytosis of AC9 and its contribution to a B2AR-mediated cAMP response from the endosome. We show that AC9 internalization is a result of Gs-coupled receptor activation, but more specifically that Gs activation is necessary and sufficient for this process. The third chapter describes the troubleshooting of the cell culture and fixation protocol, and ultimately determines that AC9 trafficking is sensitive to acute exposure to a negative CO2 gradient. The fourth chapter is a discussion of these findings, future directions and implications on the field.

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