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Adhesion GPCRs in development and cell  polarity

Multicellular organisms are highly dependent on their cells to be spatially organised to form different tissues and organs and to develop/maintain specialised functions. For this organisation cells require a sense of orientation and a form of polarity. Various types of polarity are involved in realising these processes and it is becoming increasingly clear that Adhesion GPCRs (aGPCRs) are vital players with one group of them being Latrophilins. The Latrophilin homologue LAT-1 in C. elegans is a regulator for oriented cell division in the early embryo as well as for correct reproductive system function. We use the nematode C. elegans to delineate and understand the roles of aGPCRs in development and cell polarity. C. elegans is ideal for these studies as it is a transparent self-fertilising organism which is very well characterised and offers a vast spectrum of transgenesis and genetic techniques.

Figure 1

modified from Langenhan et al., 2009 and Prömel et al., 2012

 Adhesion GPCRs in metabolic processes

Adhesion GPCRs are an intriguing class of receptors. With 33 members in mammals they form the second largest group of GPCRs, but also a poorly understood one. Several aGPCRs have implications in the control of metabolic processes. We aim to uncover the physiological functions several of these receptors play in regulating fat and insulin metabolism as well as kidney function.  Thereby, one main focus is on Latrophilins, GPR110, GPR111 and GPR115, which have for instance been shown to regulate insulin release or liver metabolism.

Figure 2

Molecular mechanisms of Adhesion GPCR activation/activity and their involvement in cellular processes

Adhesion GPCRs are not only functionally highly diverse receptors. They also display unique structural features that set them apart from other GPCRs. They are often described as hybrids fulfilling dual roles in adhesion and signalling. Besides a seven transmembrane domain (7TM) their characteristic features are their extraordinarily long N termini encompassing various domains associated with cell adhesion etc.  Via these extracellular entities aGPCR mediate different functions:  classical G protein signals but also functions solely dependent  on the N terminus which are highly unusual for GPCRs.
One main focus of our work is to understand how aGPCRs mediate these numerous signals and the role the extraordinarily long and complex N termini play. Using Latrophilins as prototypic members of the class in the versatile model organism C. elegans we have identified that the receptor functions in two different modes in different physiological contexts. One mode relays a signal via a classical G protein-mediated cascade (7TM-dependent/cis), the second one is only dependent on the receptor´s N terminus (7TM-independent/trans). The signals behind these modes and their impact are currently one of our main research topics. Similarly, we are elucidating the activation and signal transduction mechanisms of other aGPCRs.


modified from Prömel et al., 2012