Heterologous desensitization of the human dopamine D1 receptor in Y1 adrenal cells and in a desensitization-resistant Y1 mutant.

In previous studies, mutant clones (designated Y1DR) were isolated that resisted ACTH-induced homologous desensitization of adenylyl cyclase. The Y1DR mutation also conferred resistance to the homologous desensitization induced by agonist stimulation of transfected beta 2-adrenergic receptors. These observations suggested that ACTH and beta 2-adrenergic agonists homologously desensitized adenylyl cyclase in Y1 cells by a common mechanism. In the present study, parental Y1 cells (Y1DS) and the Y1DR mutant were transfected with the gene encoding the human dopamine D1 receptor and examined for regulation of adenylyl cyclase by dopaminergic agonists. Transformants were isolated from both cell lines and shown to respond to dopamine agonists with increases in adenylyl cyclase activity. Treatment of the Y1DS transformants with ACTH promoted a rapid, homologous desensitization of adenylyl cyclase and had little effect on the responses to dopamine or NaF; treatment of Y1DS with dopaminergic agonists promoted a slower rate of heterologous desensitization that diminished responsiveness of the adenylyl cyclase system to dopamine, ACTH, and NaF. Y1DR cells transfected with the dopamine D1 receptor were resistant to the heterologous desensitization of adenylyl cyclase induced by dopaminergic agonists. These latter observations suggest that the pathways of homologous desensitization and heterologous desensitization converge at a common point in the desensitization pathway defined by the DR mutation in Y1 cells.