The rat D₄ dopamine receptor couples to cone transducin (Gα(t2)) to inhibit forskolin-stimulated cAMP accumulation

Based on its expression pattern and pharmacology, the D₄ dopamine receptor may play a role in schizophrenia. Thus it is of interest to know what signaling pathways are utilized by this receptor. Previously, we showed that activation of D₄ receptors in a mouse mesencephalic neuronal cell line (MN9D) inhibited forskolin-stimulated cAMP accumulation in a pertussis toxin- sensitive (Ptx-sensitive) fashion. Of the known Ptx-sensitive G-protein α subunits, MN9D-expressed Gα(t2), Gα(oA), and Gα(oB); however, none of these coupled to the D₄ receptor. Using a low stringency polymerase chain reaction cloning method, we found an additional Ptx-sensitive G-protein cone transducin (Gα(t2)) expressed in the MN9D cells. We also found that Gα(t2) mRNA is highly expressed in rat mesencephalic tissue. To test the hypothesis that the D₄ receptor couples to Gα(t2), we cotransfected MN9D cells with the D₄ receptor and a mutagenized Ptx-resistant Gα(t2) subunit (mGα(t2)). Application of the dopaminergic agonist quinpirole to cotransfected cells inhibited forskolin-stimulated cAMP accumulation in the presence or absence of Ptx. To our knowledge, this is the first report demonstrating that the D₄ dopamine receptor functionally couples to a specific G-protein and that a non-opsin-like receptor can couple with a transducin subunit.