DIFFERENTIAL EFFECT OF HIGH EXTRACELLULAR CA2- CONDUCTANCES IN MURINEOSTEOCLASTS( ON K+ AND CL)

Effects of the extracellular Ca2+ concentration ([Ca2+](o)) on whole c ell membrane currents were examined in mouse osteoclastic cells genera ted from bone marrow/stromal cell coculture. The major resting conduct ance in the presence of 1 mM Ca2+ was mediated by a Ba2+-sensitive, in wardly rectifying K+ (IRK) current. A rise in [Ca2+](o) (5-40 mM) inhi bited the IRK current and activated an 4,4'-diisothiocyano-2,2'-stilbe nedisulfonate (DIDS)-sensitive, outwardly rectifying Cl- (ORCl) curren t. The activation of the ORCl current developed slowly and needed high er [Ca2+](o) than that required to inhibit the IRK current. The inhibi tion of the IRK current consisted of two components, initial and subse quent late phases. The initial inhibition was not affected by intracel lular application of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) or guanosine 5'-O-(2-thiodiphosphate) (GDP gamma S). The late inhibit ion, however, was enhanced by GTP gamma S and attenuated by GDP beta S , suggesting that GTP-binding proteins mediate this inhibition. The ac tivation of the ORCl current was suppressed by pretreatment with pertu ssis toxin, but not potentiated by GTP gamma S. An increase in intrace llular Ca2+ level neither reduced the IRK current nor activated the OR Cl current. Staurosporine, an inhibitor for protein kinase C, did not modulate the [Ca2+](o)-induced changes in the IRK and ORCl conductance s. These results suggest that high [Ca2+](o) had a dual action on the membrane conductance of osteoclasts, an inhibition of an IRK conductan ce and an activation of an ORCl conductance. The two conductances modu lated by [Ca2+](o) may be involved in different phases of bone resorpt ion because they differed in Ca2+ sensitivity, temporal patterns of ch anges and regulatory mechanisms.