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Cross‐talk of parathyroid hormone‐responsive dual signal transduction systems in osteoblastic osteosarcoma cells: Its role in PTH‐induced homologous desensitization of intracellular calcium response
Author(s) -
Sugimoto Toshitsugu,
Ikeda Kazuto,
Kano Junichi,
Yamaguchi Toru,
Fukase Masaaki,
Chihara Kazuo
Publication year - 1994
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.1041580220
Subject(s) - protein kinase c , parathyroid hormone , forskolin , endocrinology , medicine , homologous desensitization , pertussis toxin , cholera toxin , activator (genetics) , phorbol , calcium , chemistry , protein kinase a , desensitization (medicine) , signal transduction , calcium in biology , receptor , kinase , biology , stimulation , g protein , biochemistry
The present study was designed to characterize the cross‐talk of parathyroid hormone (PTH)‐responsive dual signal transduction systems (cAMP‐dependent protein kinase (PKA) and calcium/protein kinase C [PKC]) and its participation in PTH‐induced homologous desensitization of intracellular calcium ([Ca 2+ ]i) in osteoblastic UMR‐106 cells. Although our recent study revealed that prolonged (more than 2 h) pretreatment with PKC‐activating phorbol ester, phorbol 12‐myristate 13‐acetate (PMA) significantly decreased the PTH‐stimulated cAMP production, pretreatment with PMA (10 −7 and 10 −6 M) but not 10 −6 M 4alphaphorbol 12,13‐didecanoate (PDD), incapable of activating PKC for 30 min significantly augmented 10 −7 M hPTH‐(1‐34)‐stimulated cAMP production. H‐7 (50 uM), a PKC inhibitor, significantly antagonized this PMA‐induced effect. Pretreatment with 10 −6 M PMA for 30 min did not affect PTH receptor binding but significantly augmented a cAMP responsiveness to 10 −5 M forskolin and 1 ug/ml cholera toxin. Pertussis toxin (0.5 ug/ml) did not affect the PMA‐induced augmentation of the PTH‐stimulated cAMP production. PTH caused a complete homologous desensitization of [Ca 2+ ]i response within 30 min. Pretreatment with 10 −4 M dibutyryl cAMP for 30 min and 6 h significantly reduced and completely blocked the PTH‐induced increase in [Ca 2+ ]i, respectively. Pretreatment with 10 −4 M Sp‐cAMPS, a direct PKA activator, for 30 min completely blocked the PTH‐induced increase in [Ca 2+ ]i. Rp‐cAMPS (10 −4 M), an antagonist of PKA, slightly but significantly antagonized the PTH‐induced homologous desensitization of [Ca 2+ ]i response. The present study indicates that the time of exposure to PKC activation is a critical determinant in modulating the cAMP system, while PKA activation counterregulatorily acts on the [Ca 2+ ]i system, and that PKA activation is linked to the PTH‐induced homologous desensitization of [Ca 2+ ]i response. © 1994 Wiley‐Liss, Inc.