Astrocyte morphology altered by 1-(5-isoquinolinylsulfonyl) 2-methyl piperazine (H-7) and other protein kinase inhibitors.
Studies were conducted to determine if the protein kinase C inhibitor H-7 could block the effects of phorbol-12-myristate-13-acetate (PMA) on astrocyte morphology. Contrary to expectation, H-7 alone was found to induce morphological changes very similar to those elicited by PMA. This effect was shared by two other inhibitors of protein kinase C, H-8 and staurosporine, but not by the cyclic nucleotide-dependent protein kinase inhibitor HA-1004 or the calcium/calmodulin dependent protein kinase inhibitor W-7. Although the morphological effects observed with H-7 resemble those induced by PMA, H-7 did not promote the redistribution of protein kinase C to the membrane or induce the phosphorylation of endogenous proteins like PMA. In addition, the effects of H-7 were still observed in cells depleted of protein kinase C activity which were no longer responsive to treatment with PMA. Cytoskeletal elements appear to be involved in the effect of H-7 on cell shape since this effect is blocked by treatment with colchicine. Activators of the cyclic AMP-dependent protein kinase also alter astrocyte shape, however, while H-7 did cause a slight increase in cyclic AMP levels, it was unlikely that this action is responsible for its effect on morphology. One common action of both H-7 and PMA was to decrease the 32P content of several 20,000 Da proteins. While the mechanism by which H-7 exerts its influence on astrocyte morphology remains to be clarified, be it by the inhibition of protein kinase C or some other mechanism, the results suggest that caution must be used when interpreting the effects of activators and inhibitors of this kinase.
Bedoy
C A
CA
St. Mary's University, San Antonio, TX 78284.
Mobley
P L
PL
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D008970:Molecular Weight; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013110:Sphingosine / Q000494:pharmacology; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D010879:Piperazines; D011506:Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000242:Cyclic AMP; D011493:Protein Kinase C; D019311:Staurosporine; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate