Identification of protein phosphatase 2A as the primary target for microcystin‐LR in rat liver homogenates

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Abstract
The liver‐specific toxin microcystin‐LR (MC‐LR) is a potent inhibitor of type 1 (PP1) and type 2A (PP2A) protein phosphatases. A tritiated form of the toxin, [3H]dihydromicrocystin‐LR ([3H]DMC‐LR), was used to identify target proteins in cellular fractions prepared from rat liver homogenates. About 80% of the [3H]DMC‐LR bound to proteins was in the cytosolic fraction, which contained essentially all of the PP2A. In contrast, much of the PP1 was found in particulate fractions, each with only a few percent of the total protein‐bound [3]HDMC‐LR. Protein‐bound [3H]DMC‐LR in the cytosol co‐eluted with PP2A, but not with PP‐1 from a DEAE‐Sepharose column. Native forms of liver cytoplasmic PP2A and PP1 separated by aminohexyl‐Sepharose adsorption showed similar sensitivity to inhibition by MC‐LR, and bound [3H]DMC‐LR proportional to the amount of phosphatase activity. The results indicate that [3H]DMC‐LR can bind both PP2A and PP1 in the liver which must be important for microcystin‐induced toxicity, but is recovered mainly bound to PP2A in the cytosol.

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