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Protein kinase C regulates the internalization and function of the human organic anion transporting polypeptide 1A2

Fanfan Zhou1, Andy C Lee, Katja Krafczyk

  • 1Pharmacogenomics and Drug Development Laboratory, Faculty of Pharmacy, The University of Sydney, Australia. fanfan.zhou@sydney.edu.au

British Journal of Pharmacology
|December 8, 2010
PubMed
Abstract

Insights

Protein kinase C (PKC) activation reduces the function of the organic anion transporting polypeptide 1A2 (OATP1A2) by increasing its internalization via clathrin-dependent pathways.

Area of Science:

  • Cellular Biology
  • Molecular Transport
  • Pharmacology

Background:

  • The human organic anion transporting polypeptide 1A2 (OATP1A2) facilitates the transport of anionic substances, including drugs, across cell membranes.
  • OATP1A2 is expressed in critical tissues such as the kidney, cholangiocytes, and the blood-brain barrier.
  • Post-translational modifications, like kinase-induced internalization, are known to regulate mammalian transporters.

Purpose of the Study:

  • To investigate the role of protein kinase C (PKC) in regulating the function and localization of OATP1A2.
  • To determine if PKC activation affects OATP1A2 transport activity and cell surface expression.

Main Methods:

  • Overexpression of OATP1A2 in COS-7 cells.
  • Treatment with a PKC activator (PMA) and a PKC inhibitor (Go6976).
  • Assessment of OATP1A2 transport function, cell surface expression, and internalization pathways (clathrin- and caveolin-dependent).

Main Results:

  • PKC activation significantly decreased OATP1A2 transport function in a time- and concentration-dependent manner.
  • PMA treatment reduced OATP1A2 Vmax and cell surface expression, effects reversed by Go6976.
  • PKC activation accelerated OATP1A2 internalization, primarily through clathrin-dependent endocytosis, without affecting recycling.

Conclusions:

  • Protein kinase C (PKC) negatively regulates OATP1A2 transport activity.
  • PKC-mediated regulation occurs through enhanced internalization of OATP1A2.
  • Clathrin-dependent endocytosis is a key pathway involved in PKC-modulated OATP1A2 internalization.

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