A possible molecular mechanism for β-receptor desensitization: Experiments and hypotheses

β-Receptor desensitization in intact NRK-S cells and in a crude membrane preparation derived from these cells was found not to involve methylation, cAMP dependent phosphorylation, Ca⁺⁺ dependent phosphorylation or ADP ribosylation, but is absolutely dependent on ATP in cell-free systems. Also, the desensitized state could not be relieved by protein phosphatases or alkaline phosphatases. Depletion of intact cells from ATP by prolonged incubation with 2-deoxy-glucose and NaN₃ did not inhibit the rapid onset of desensitization by incubating the cells with β-agonists. In order to rationalize the two seemingly contradictory findings, namely, the absolute requirement of ATP in the cell-free desensitization system and the inability to reverse the desensitized state by a variety of phosphatases, we propose that the uncoupling reaction responsible involve for establishing the desensitized state does not Our working hypothesis suggests instead, that the uncoupling reaction involves a covalent modification of the receptor protein and is catalyzed by a receptor modulator protein which is under the control of the ATP dependent phosphorylation.