PKC (19-36), a selective PKC peptide inhibitor

2018-09-21

Introduction 

PKC (19-36), a synthetic peptide of the pseudosubstrate domain of the kinase, is a selective inhibitor of protein kinase C (PKC).

Pharmacologic action

PKC (19-36), a pseudosubstrate prototope (amino acid residues 19-36) of PKC, is a conserved region of the regulatory domain of the PKC family, which is a potent pseudosubstrate blocker of PKC activity. In unfertilized eggs, maintenance of pH appeared to be independent of protein kinase activities. The pHi remained stable in eggs injected with PKC (19-36) during the incubation period of up to 90 minutes, which is similar to the observational results with protein kinase inhibitors. Since the removal of external Na+ or addition of amiloride, an inhibitor of Na+-H+ antiporter causes cytoplasmic acidification, basal activity of the antiporter appears to be independent of protein kinase activities. It remains unclear that how the antiporter activity is altered by protein kinase activity, wich is stimulated during fertilization. The experiment results suggest that coupling between sperm-egg fusion and activation of the Na+-H+ antiporter involves multiple second messenger pathways.

Function

It has been reported that PKC (19-36) could block PKC activity without blocking Ca 2+ -CaM-dependent kinase activity both in vivo and in vitro. Besides, PKC (19-36) blocked Ca2+, phosphatidylserine and 1,2-diacylglycerol-dependent (DAG-dependent) phosphorylation of 40-60 % endogenous substrates in a preliminary in vitro assay. Experiment that PKC (19-36) blocked PMA-induced rise of pHi suggests that the synthetic peptide is active in intact eggs. And the addition of 4.8 μM PKC (19-36) inhibited 90% of Ca2+-stimulated phosphorylation of P17 in CAI homogenates. PKC (19-36) blocked the increase in LTP-associated protein phosphorylation and caused a decrease in phosphorylation of P17 in control homogenates. Furthermore, PKC (19-36) had no significant effect on CaMKII autophosphorylation visualized on autoradiograms.

Pharmacokinetics and metabolism

The effects of the synthetic peptide PKC (19-36) on activation of the Na+-H+ antiporter was tested by either fertilization or treatment with PMA. During fertilization or PMA activation, there is no immediate effect of injecting 2 to 20 μM PKC (19-36) on cytoplasmic alkalinization. However, if activation of the egg is delayed >30 min postinjection, injection of 2 to 20 μM PKC (19-36) will have a significant effect on cytoplasmic alkalinization. The rise in pHi is increasingly reduced as the concentration of PKC (19-36) injection increased during egg activation by fertilization or PMA treatment.

References:

1. Shen, S. S., & Buck, W. R. (1990). A synthetic peptide of the pseudosubstrate domain of protein kinase C blocks cytoplasmic alkalinization during activation of the sea urchin egg. Developmental biology, 140(2), 272-280.

2. Klann, E., Chen, S. J., & Sweatt, J. D. (1992). Increased phosphorylation of a 17‐kDa protein kinase C substrate (P17) in long-term potentiation. Journal of neurochemistry, 58(4), 1576-1579.

3. Yasunari, K., Kohno, M., Kano, H., Yokokawa, K., Horio, T., & Yoshikawa, J. (1996). Possible involvement of phospholipase D and protein kinase C in vascular growth induced by elevated glucose concentration. Hypertension, 28(2), 159-168.

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