Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers

G protein-coupled receptors (GPCRs) transmit signals by forming active-state complexes with heterotrimeric G proteins. It has been suggested that some GPCRs also assemble with G proteins prior to ligand-induced activation, and that inactive-state preassembly facilitates rapid and specific G protein activation. However, no mechanism of preassembly has been described, and no functional consequences of preassembly have been demonstrated. Here we show that M(3) muscarinic acetylcholine receptors (M3R) form inactive-state complexes with G(q) heterotrimers in intact cells. The M3R C terminus is sufficient, and a six amino-acid polybasic sequence distal to helix 8 (565KKKRRK570) is necessary for preassembly with G(q). Replacing this sequence with six alanine residues prevents preassembly, slows the rate of G(q) activation, and decreases steady-state agonist sensitivity. Other G(q)-coupled receptors possess similar polybasic regions and also preassemble with G(q), suggesting that these GPCRs may utilize a common preassembly mechanism to facilitate activation of G(q) heterotrimers.