PROTEIN-KINASE-C IS INVOLVED IN PTH-INDUCED HOMOLOGOUS DESENSITIZATION BY DIRECTLY AFFECTING PTH RECEPTOR IN THE OSTEOBLASTIC OSTEOSARCOMA CELLS

被引:40
作者
IKEDA, K [1 ]
SUGIMOTO, T [1 ]
FUKASE, M [1 ]
FUJITA, T [1 ]
机构
[1] KOBE UNIV,SCH MED,DEPT MED,DIV 3,KOBE 650,JAPAN
关键词
D O I
10.1210/endo-128-6-2901
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We have investigated mechanisms of PTH-induced homologous desensitization reflected in the refractoriness of cAMP response to the second exposure to PTH in the clonal rat osteosarcoma cell line, UMR-106. Preincubation with 10(-7) M rat (r) PTH-(1-34) for 6 h caused the desensitation, resulting in a 65% decrease in cAMP accumulation in response to further exposure to rPTH. This desensitization was apparent at 10(-10) M rPTH and maximal at 10(-7) M rPTH. UMR-106 cells treated with protein kinase C (PK-C) activating phorbol ester, phorbol 12-myristate 13-acetate (PMA, 10(-6) M) for 6 h also induced desensitization manifested by a loss of rPTH-stimulated cAMP accumulation to 50% of that in the control cells. On the other hand 4-alpha-phorbol 12,13-didecanoate, incapable of activating PK-C, failed to induce desensitization. Fifty micromolar H-7 (PK-C inhibitor) significantly blocked both rPTH- and PMA-induced desensitization. Thus, PK-C seemed to play a major role in rPTH-induced desensitization. Pretreatment with neither rPTH nor PMA changed the cAMP responsiveness to 10-mu-g/ml cholera toxin or 100-mu-M forskolin. Islet activating protein failed to influence the desensitization in this cell line. PTH receptor binding, assessed by using I-125-labeled [Nle8,Nle18,Tyr34]PTH-(1-34) as a radioligand, was decreased along with PTH receptor numbers by pretreatment with rPTH or PMA. These data indicate that rPTH-induced homologous desensitization occurs at least in part through the activation of PK-C and that PK-C directly affects PTH receptor in UMR-106 cells.
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页码:2901 / 2906
页数:6
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