INHIBITORS OF PROTEIN KINASE-C MODULATE DESENSITIZATION OF THE PARATHYROID-HORMONE RECEPTOR-ADENYLATE CYCLASE SYSTEM IN OPOSSUM KIDNEY-CELLS

被引:49
作者
PERNALETE, N
GARCIA, JC
BETTS, CR
MARTIN, KJ
机构
[1] ST LOUIS UNIV,MED CTR,DIV NEPHROL,3635 VISTA AVE & GRAND BLVD,POB 15250,ST LOUIS,MO 63110
[2] WASHINGTON UNIV,SCH MED,DEPT INTERNAL MED,DIV RENAL,ST LOUIS,MO 63110
关键词
D O I
10.1210/endo-126-1-407
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The mechanisms involved in mediating desen-sitization and down-regulation of renal PTH receptors have not been defined. Recent studies indicate that PTH binding pro-motes not only stimulation of adenylate cyclase and activation of protein kinase-A (PK-A), but also, stimulation of phospholi- pase-C, leading to activation of PK-C. PK-C has been shown to alter both receptor and adenylate cyclase function in other systems. Therefore, the present studies were conducted to test whether PK-C might play a role in the regulation of the PTH receptor-cyclase system after exposure to PTH. Exposure of confluent cultures of opossum kidney (OK) cells to rat PTH-(1- 34) (100 nM) for 6 h resulted in a 48 ± 8% (n = 5) decrease in stimulation of cAMP accumulation in response to further ex-posure to PTH. PTH receptor binding, assessed with125I- [Nle8, Nle21 Tyr34]rat PTH-(1-34)NH2 as radioligand, was de-creased to a similar extent. Phorbol ester (4β-12, 13-didecanoate; 1 μM) treatment of the cells in the absence of PTH caused a 58 ± 3% decrease in PTH-stimulated cAMP production, but equilibrium PTH receptor binding was not different from the control value. Both 50 M H-7 and 0.5 μM Staurosporine (inhibitors of PK-C) completely blocked the effects of phorbol ester. Pretreatment with PTH, however, in the presence of H-7 or Staurosporine resulted in a completely normal cAMP response to restimulation with PTH. Thus, two inhibitors of PK-C completely prevented desensitization to PTH. The decrease in equilibrium PTH binding, seen after incubation with PTH alone, was also blunted by the inhibitors of PK-C. These data indicate that activation of PK-C by stimulation with PTH may play a role in the regulation of the PTH receptor-cyclase system in OK cells. © 1990 by The Endocrine Society.
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页码:407 / 413
页数:7
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