D1 dopamine receptor activity is not altered by a mutation in the first intracellular loop.

The first intracellular loop of the G protein-coupled receptors (GPCRs) is probably the domain that has been studied least. According to the limited data available, mutations of this region can increase, decrease or not affect receptor-G protein coupling, depending on the receptor. Melanocyte-stimulating hormone (MSH) receptors with a Ser69Leu mutation of the first intracellular loop phenotypically confer tobacco color to the coat of mice, and have constitutive activity and enhanced agonist stimulation of adenylyl cyclase. Since the human D1 dopamine receptor (D1DR) has a serine at the equivalent position, we were interested to see if this serine is involved in receptor-G protein coupling in a similar fashion. Our site-directed mutagenesis study showed that the replacement of this serine by leucine (Ser56Leu) in D1DR did not affect the ability of the receptors to bind ligand or couple to G protein.