Structural Requirements of Lyngbyatoxin A for Activation and Downregulation of Protein Kinase C

Alakananda Basu, John S. Lazo, Alan P. Kozikowski

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Structure-activity studies of novel synthetic analogues of lyngbyatoxin A reveal that the lactam ring but not the 7-linalyl moiety of lyngbyatoxin A is essential for the in vitro stimulation of protein kinase C (PKC). (-)-Indolactam V (ILV), which contains no hydrophobic substituent at C-7, or analogues containing either a linalyl or n-hexyl group at C-7 were equally efficacious in stimulating HeLa cell PKC in vitro and in competing with phorbol 12, 13-dibutyrate for binding to PKC in intact cells. The hydrophobicity of alkyl groups at C-7, however, influenced the potency of these compounds to bind to and activate PKC. In addition, these compounds exhibited differences in their ability to translocate PKC. Lyngbyatoxin A (0.1 μM) like TPA induced a rapid translocation of PKC from the cytosol to the membrane and subsequently led to a sustained decrease in both cytosolic and membrane PKC activity. In contrast, (-)-n-hexyllLV (0.1 μM) and (-)-ILV (1 μM) produced a transient and attenuated decrease in cytosolic PKC activity. At concentrations that produced half-maximal PKC stimulation, (-)-ILV did not cause any downregulation of PKC whereas lyngbyatoxin A and (-)-n-hexyllLV led to 60% and 40% PKC downregulation, respectively. Western blot analyses with monoclonal antibodies to PKC isoforms indicated that reduction in PKC activity by chronic exposure to TPA or lyngbyatoxin A analogues could be explained by downregulation of PKCa. Constitutive expression of PKCΒ and PKCΓ isoforms was low in HeLa cells and was not affected significantly by TPA or lyngbyatoxin A analogues. These results indicate that the structural requirements for PKC activation may be separated from those required for PKC downregulation.

Original languageEnglish
Pages (from-to)3824-3830
Number of pages7
Issue number15
StatePublished - 1 Apr 1992


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