Maria Hauge Pedersen
Section for Metabolic Receptology
2200 København N
Abstract for my PhD project:
Background - 7TM receptors constitute the largest family of membrane proteins. They mediate their signal
through coupling to different G proteins, as well as through G protein independent, for example arrestinmediated
pathways. In recent years it has become clear that especially synthetic drug-like ligands can signal
in a signal transduction pathway-biased way, i.e. for example the ligand may exclusively activate one
pathway without affecting another pathway normally used by the endogenous ligand. Such biased signaling
property is important in dug development to obtain certain effects and for example avoid certain sideeffects.
It is evident that in a given cell the individual 7TM receptors must act in concert with a number of other
7TM receptors, however, in most cases the molecular pharmacology and signaling properties of the
receptors have been studied with a view of the receptors as being 'alone' or they have been studied in
respect of dimidiation but very infrequently based on insight in the receptors normal functional 'partners'.
The present project is based on detailed knowledge about the co-expression on enteroendocrine cells of
three structurally distinct but functionally related sensors for triglyceride metabolites. Enteroendocrine
cells are the hormone secreting cells of the enteroendocrine system. The triglycerides in the dietary fat are
degraded by pancreatic lipase into long chain fatty acids and 2-monoacylglycerol which are detected by
GPR120 and GPR40 and by GPR119, respectively. These three receptors are co-expressed and highly
enriched on enteroendocrine cells.
Aim of the Study: To characterize the basic molecular pharmacological and cell biological interactions
between three functionally related 7TM receptors, GPR119, GPR40 and GPR120, which are co expressed
and conceivably co-function as chemosensors for metabolites of triglycerides.
A major hypothesis is that these three fat-sensors, which each recognizes distinct metabolites of dietary
triglycerides and which are co-expressed on, for example enteroendocrine cells, function in concert
through close interactions both at the molecular level and at the cell biological, signal transduction level.