Hanai H, Liang C T, Cheng L, Sacktor B
Laboratory of Biological Chemistry, National Institute on Aging, Baltimore, Maryland 21224.
J Clin Invest. 1989 Jan;83(1):268-77. doi: 10.1172/JCI113869.
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.
老年大鼠肾皮质细胞中，甲状旁腺激素（PTH）刺激的Na⁺/Ca²⁺交换活性减弱，但福斯高林敏感的Na⁺依赖性Ca²⁺外流未受影响。衰老大鼠肾膜中PTH敏感的腺苷酸环化酶活性也下降，但福斯高林刺激的活性未改变。此外，老年动物细胞中霍乱毒素和百日咳毒素刺激的Na⁺依赖性Ca²⁺外流及cAMP生成减弱。此外，通过ADP核糖基化检测发现，老年大鼠细胞中Gs-α和Gi-α蛋白减少。这些发现与涉及G蛋白的年龄相关异源脱敏的提议一致。老年大鼠血清中免疫反应性甲状旁腺激素（iPTH）浓度升高，表明衰老大鼠对PTH的脱敏代表了对该激素长期刺激的适应性反应。甲状旁腺切除可逆转老年大鼠细胞中减弱的PTH敏感的Na⁺/Ca²⁺交换活性、cAMP生成及腺苷酸环化酶活性，这一发现支持了该假说。手术也很大程度上消除了老年大鼠细胞中霍乱毒素催化的ADP核糖基化Gs-α和百日咳毒素催化的ADP核糖基化Gi-α中减少的标记。总之，结果表明肾细胞对PTH反应的年龄相关减弱与G蛋白功能缺陷有关，且这种改变可通过切除甲状旁腺来逆转。
