New Modes of GPCR Signalling

ABSTRACT
New Modes of GPCR Signalling
Joel Bockaert, Federica Bertaso, Carine Becamel, Maryline Labasque, Mireille
Lerner-Natoli, Laurent Fagni, Philippe.Marin.
CNRS UMR5203,Institut de Génomique Fonctionnelle,Montpellier,France,INSERM,
U661,Montpellier France and University of Montpellier
For a long time, we thought that GPCRs were part of a two-dimentional signaling
pathways. It was believed that ligand-activated GPCRs were only activating one or a
limited number of heterotimeric G proteins . However, since according to Paul Valery
« what is simple is certainly wrong » the control of cell physiology by GPCRs is far
more complex. We will illustrate, with 3 examples, this complexity. The first one
concerns a new type of transactivation between GPCRs and receptor tyrosine kinases
(RTKs). Classically GPCRs are known to be transactivated by RTKs. However, there
are some examples of the reverse situation. Indeed we provide data showing that
IGF-Rs transactivate PACAP-Rs in neurons. Phosphorylation of PACAP-Rs, induced
by IGF1, lead to un-liganded PACAP-Rs activation and their coupling to Gs. The
second one is the key role of GPCR-associated signalling in fine-tuning of their
signalling. mGluR7 negatively control the P/Q channels of pre-synaptic terminals an
effect which require absolutely the physical association of their c-terminal PDZ ligand
with PICK1. We have shown, in vivo, that disconnecting mGluR7 from PICK1 (with
cell-permeant dominant-negative peptide and knock-in mice) causes absence-like
seizures. The third one is the illustration that GPCRs can signal without any G
activation. This will be illustrated here by showing that long-lasting (one hour)
activation of ERK pathway by 5-HT2c-Rs is mediated via a complex formed by the
receptor C-terminal associated and calmodulin and -arrestin.