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Interaction of parathyroid hormone‐related peptide‐responsive dual signal transduction systems in osteoblastic osteosarcoma cells: Role in PTHrP‐induced homologous desensitization
Author(s) -
Sugimoto Toshitsugu,
Kano Junichi,
Ikeda Kazuto,
Fukase Masaaki,
Chihara Kazuo
Publication year - 1993
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.5650080409
Subject(s) - desensitization (medicine) , parathyroid hormone , osteosarcoma , signal transduction , homologous chromosome , medicine , endocrinology , cancer research , chemistry , homologous desensitization , transduction (biophysics) , peptide , microbiology and biotechnology , biology , receptor , calcium , biochemistry , gene
In Osteoblastic Umr‐106 Cells, 10 −7 M human (h) PTH‐related peptide (PTHrP)‐(1–34) significantly induced the formation of total inositol phosphates to the same degree as 10 −7 M hPTH‐(1–34), confirming that in addition to cAMP‐dependent protein kinase (PKA), PTHrP possesses another signal transduction system, calcium/protein kinase C (Ca/PKC). Experiments were therefore performed to characterize the cross talk of these dual‐signal transduction systems and its participation in the PTHrP‐induced homologous desensitization of cAMP and cytosolic calcium (Ca i ) response in osteoblasts. Preincubation with 10 −7 M hPTHrP‐(1–34) caused homologous desensitization, resulting in a remarkable decrease in cAMP accumulation in response to further exposure to PTHrP. This effect was significant after 2 h pretreatment and reached a maximum at 6 h. Pretreatment with the PKC‐activating phorbol ester phorbol 12‐myristate‐13‐acetate (PMA, 10 −6 M) for 30 minutes and 6 h caused a significant increase and decrease in cAMP responsiveness to PTHrP, respectively. Pretreatment with calcium ionophores (A23187 or ionomycin, 10 −6 M), not for 30 minutes but for 6 h, caused a significant decrease in cAMP responsiveness to PTHrP. H‐7 (an inhibitor of PKC, 50 μM) significantly blocked not only PMA‐ but also PTHrP‐induced desensitization of the cAMP response. PTHrP caused the complete homologous desensitization of an increase in Ca i within 30 minutes. Pretreatment with dibutyryl‐cAMP (10 −4 M) for 30 minutes caused significant inhibition of the PTHrP‐induced increase in Ca i , and pretreatment with Sp‐cAMPS (10 −4 M), a direct activator of PKA, for 30 minutes completely blocked the PTHrP‐induced increase in Ca i . Rp‐cAMPS (10 −4 M), an antagonist in the activation of PKA, slightly but significantly antagonized the PTHrP‐induced homologous desensitization of the Ca i response. The present study demonstrated the existence of cross‐talk in PTHrP‐responsive dual signal transduction systems and its participation in PTHrP‐induced homologous desensitization.