Researchers
from a CNRS laboratory in Montpellier, known as M2C2 ("Mécanismes
moléculaires des communications cellulaires," Molecular
Mechanisms of Cellular Communication), have teamed up with neurobiologists
at Johns Hopkins University and Bayer laboratories to investigate
the activation of neuronal glutamate receptors.
These
researchers showed that receptors in the brain can be activated by
proteins within the cell in the absence of extracellular signals.
The mGluR1a and mGluR5 receptors are members of the vast family of
G protein coupled receptors (GPCR) and are targeted by many neuro-modulatory
drugs. The mGluR receptors are normally activated by binding to extracellular
glutamate. The CNRS researchers found that they can also be modulated
by interactions with intracellular proteins. They identified a family
of proteins (called Homer1, Homer2 and Homer3) in neurons. When they
blocked the interaction between mGluR1a and Homer3, the receptor became
constitutively active. A mutated isoform of mGluR5 failed to interact
with Homer 3 and was also constitutively active. In addition, neuronal
activity induces the synthesis of a short form of Homer, Homer 1a,
that uncouples Homer 3 from the mGluR1a receptor and activates the
receptor. Compounds that modify the mGluR-Homer interactions may serve
as useful pharmacological agents.
