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 (Cai) 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 pretreament 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 microM) significantly blocked not only PMA- but also PTHrP-induced desensitization of the cAMP response. PTHrP caused the complete homologous desensitization of an increase in Cai within 30 minutes. Pretreatment with dibutyryl-cAMP (10(-4) M) for 30 minutes caused significant inhibition of the PTHrP-induced increase in Cai, and pretreatment with Sp-cAMPS (10(-4) M), a direct activator of PKA, for 30 minutes completely blocked the PTHrP-induced increase in Cai.(ABSTRACT TRUNCATED AT 250 WORDS)