Coupling profile of the metabotropic glutamate receptor 1alpha is regulated by the C-terminal domain

The metabotropic glutamate receptor 1alpha (mGluR1alpha) is known to cause various cell responses via coupling with different types of G protein. By using a combination of fluorescent indicators, we simultaneously observed the dual signals of mGluR1alpha, via activation of the Gq and Gs proteins, as increases in the intracellular Ca(2+) and cAMP concentration, respectively. The dual signals are regulated by long C-terminal domain of mGluR1alpha since a short splice variant, mGluR1beta, could not activate the Gs pathway. Cytoskeletal proteins that interact with the long C-terminal tail, such as homer1 and 4.1G, are known to modulate the mGluR1alpha signaling; however, their effects on the dual signaling remain unknown. The simultaneous monitoring demonstrated that the 4.1G behaves as a regulator of dual signaling rather than a simple inhibitor, via its interaction with a cluster of acidic residues in the distal C-tail, which locates close to the important regions for the Gs coupling.