Desensitization to parathyroid hormone in renal cells from aged rats is associated with alterations in G-protein activity.

Parathyroid hormone (PTH)-stimulated Na+/Ca2+ exchange activity, but not forskolin-sensitive Na+-dependent Ca2+ efflux, was blunted in renal cortical cells from aged rats. PTH-sensitive adenylate cyclase activity in renal membranes from senescent rats also declined, but forskolin-stimulated activity did not change. In addition, cholera toxin- and pertussis toxin-stimulated Na+-dependent Ca2+ efflux and cAMP formation were blunted in cells from aged animals. Further, cells from aged rats had decreased Gs-alpha and Gi-alpha proteins, as detected by ADP-ribosylation. These findings would be consistent with the proposal of an age-associated heterologous desensitization that involved the G-proteins. Serum concentrations of iPTH were increased in the old rat, suggesting that the desensitization to PTH in the aging rat represented an adaptive response to prolonged stimulation by the hormone. This hypothesis was supported by the findings that the attenuated PTH-sensitive Na+/Ca2+ exchange activity, cAMP formation, and adenylate cyclase activity in cells from old rats could be reversed by parathyroidectomy. The decreased label in cholera toxin-catalyzed ADP-ribosylated Gs-alpha and pertussis toxin catalyzed ADP-ribosylated Gi-alpha found in cells from aged rats was also largely negated by the surgery. In conclusion, the results suggest that the age-related blunting in the responses of renal cells to PTH was associated with a deficit in G-protein function and that this alteration could be reversed by removal of the parathyroid gland.