Rare Alzheimer's Disease‐Associated Protein Kinase C Variant Displays Altered Pharmacological Profile in a Cellular Environment

Abstract

Ever since protein kinase C (PKC) was discovered as receptors for tumor‐promoting phorbol esters in the early 1980s, efforts have been made to target PKC in the treatment of disease. Here, we show that PKCα‐M489V, a rare Alzeheimer's Disease (AD)‐associated PKC variant with enhanced agonist‐evoked signaling output, displays an altered pharmacological profile compared to wild type PKCα in a cellular environment. Using a genetically encoded PKC activity reporter and a phospho‐serine PKC substrate antibody as readouts for PKC activity, we find that overexpressed PKCα‐M489V in COS7 cells is more sensitive to inhibition by the ATPcompetitive PKC inhibitor Gö6976, but not by the uncompetitive PKC inhibitor bisindolylmaleimide IV (BisIV). However, PKCα‐M489V is equally sensitive to inhibition by Gö6976 in vitro, suggesting that the difference may result from protein‐protein interactions within the cell. The altered pharmacology of the M489V variant in vivo may provide a novel method of targeting PKCs in the treatment of AD.Support or Funding InformationThis work was supported by N!H R35 GM122523 and NIH GM43154 (AN) and the Cure Alzheimer's Fund (AN). JC was supported by the UCSD Graduate Training Program in Cellular and Molecular Pharmacology (T32 GM007752).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.