An amino acid residue in the second extracellular loop determines the agonist-dependent tolerance property of the human D3 dopamine receptor.

The D3 dopamine receptor is a therapeutic target for treating various nervous system disorders such as schizophrenia, Parkinson's disease, depression, and addictive behaviors. The crystal structure of the D3 receptor bound to an antagonist was recently described; however, the structural features that contribute to agonist-induced conformational changes and signaling properties are not well understood. We have previously described the conformation-dependent tolerance and slow response termination (SRT) signaling properties of the D3 receptor and identified the C147 residue in the second intracellular loop (IL2) of the D3 receptor as important for the tolerance property.

Development of tolerance in D3 dopamine receptor signaling is accompanied by distinct changes in receptor conformation.

The D3 but not D2 dopamine receptors exhibit a tolerance property in which agonist-induced D3 receptor response progressively decreases upon repeated agonist stimulation. We have previously shown that the D3 receptor tolerance property is not mediated by receptor internalization, persistent agonist binding or a decrease in receptor binding affinity. In this paper, we test the hypothesis that alterations in D3 receptor conformation underlie the tolerance property.