Regulation of parathyroid hormone release in normal and pathological parathyroid cells exposed to modulators of protein kinase C.
Effects of the protein kinase C activating phorbol ester 12-O-tetradecanoyl phorbol 13-acetate and the inhibitor 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7) on parathyroid hormone (PTH) release were studied in normal bovine and pathological human parathyroid cells. An increase of extracellular Ca2+ from 0.5 to 3.0 mmol/l inhibited PTH release by 60% in the bovine cells with half maximal effect (ED50) at 1.31 mmol/l. This inhibition reached less than 50% in the cells from patients with primary and uremic hyperparathyroidism, and the ED50 values were 1.49 and 1.42 mmol/l, respectively. The phorbol ester (0.1 mumol/l) made secretion insensitive to changes of extracellular Ca2+, an action counteracted by H-7 (50 mumol/l) in the bovine cells, whereas H-7 alone had no effects. The phorbol ester and H-7 had opposite actions on regulation of PTH release also from cells from patients with hyperparathyroidism. However, in pathological cells H-7 alone improved Ca2+ inhibition of secretion by stimulating release in low Ca2+ concentrations and decreasing the ED50 values. The magnitude of changes in ED50 values by H-7 increased with the severity of the secretory disturbance of the pathological cells. The results indicate that increased protein kinase C activity may be a factor of importance in the pathophysiology of hyperparathyroidism.
Ridefelt
P
P
Department of Surgery, University of Uppsala, Sweden.
Nygren
P
P
Hellman
P
P
Larsson
R
R
Rastad
J
J
Akerström
G
G
Gylfe
E
E
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000236:Adenoma / Q000503:physiopathology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002417:Cattle; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology / Q000503:physiopathology; D006961:Hyperparathyroidism / Q000503:physiopathology; D006965:Hyperplasia; D007546:Isoquinolines / Q000494:pharmacology; D010279:Parathyroid Diseases / Q000473:pathology / Q000503:physiopathology*; D010280:Parathyroid Glands / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism*; D010282:Parathyroid Neoplasms / Q000503:physiopathology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014511:Uremia / Q000150:complications
D007546:Isoquinolines; D010281:Parathyroid Hormone; D010879:Piperazines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium