C-terminal deletion of metabotropic glutamate receptor 1 selectively abolishes coupling to Gαq

Recent studies indicate that the intracellular C-terminus of Group I metabotropic glutamate receptors (mGlu1 and mGlu5 receptor) is important in G protein coupling. To determine the necessity of the C-tail, a deletion mutant of mGlu1 receptor was constructed, which included the first 840 amino acids of the rat mGlu1a receptor (mGlu1-dCT). G protein coupling of the receptors was assessed by measuring glutamate mediated inhibition of native calcium currents when each receptor was expressed in isolated sympathetic neurons from the rat superior cervical ganglion. Wild type mGlu1 receptor activates both the Gαi/o and Gαq/11 protein families. Each pathway can be detected in superior cervical ganglion neurons as voltage dependent and voltage independent inhibition of the calcium currents, respectively. While wild type mGlu1 receptor gave rise to a strong, mixed voltage dependent and independent calcium current inhibition, mGlu1-dCT exhibited a weaker inhibition that was strongly voltage dependent, indicating activation of Gαi/o was predominant. Further, pertussis toxin treatment reduced the inhibition by wild type mGlu1 receptor to a smaller, voltage independent inhibition as expected, but completely abolished signaling through mGlu1-dCT. Finally, to test whether mGlu1-dCT could produce any activation of Gαq/11, inhibition of the native superior cervical ganglion M-type potassium currents was examined. M-channels, inhibited by PIP2 depletion, were strongly inhibited by glutamate in cells expressing wild type mGlu1 receptor, but no inhibition was detectable in neurons expressing mGlu1-dCT. These data indicate that C-terminal deletion of mGlu1 receptor selectively abolishes Gαq/11 coupling.