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Protein kinase inhibition differentially regulates organic cation transport

Alexander M Gerlyand1, Daniel S Sitar

  • 1Department of Pharmacology and Therapeutics, University of Manitoba, A220-753 McDermot Avenue, Winnipeg, MB R3E 0T6, Canada.

Canadian Journal of Physiology and Pharmacology
|January 7, 2010
PubMed

Insights

This study reveals distinct regulation of organic cation transporters in kidney cells. Amantadine and tetraethylammonium (TEA) transport are differentially controlled by glucose levels, bicarbonate, and cAMP, impacting kidney function in diabetes.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Physiology

Background:

  • Diabetic rats exhibit altered amantadine and tetraethylammonium (TEA) transport in kidney tissue, with changes reversed by insulin.
  • This suggests differential regulation of organic cation transporters, necessitating further investigation into the underlying mechanisms.

Purpose of the Study:

  • To investigate the differential regulation of organic cation transporters in kidney cells.
  • To elucidate the roles of glucose, bicarbonate, and cyclic AMP (cAMP) in modulating transporter activity.

Main Methods:

  • Utilized native human embryonic kidney (HEK293) cells and rat organic cation transporter (rOCT)-transfected cells.
  • Manipulated glucose levels, bicarbonate presence, and employed cAMP analogues to assess transporter responses.

Main Results:

  • Short-term glucose starvation differentially affected amantadine and TEA transport, with bicarbonate modulating amantadine transport specifically.
  • cAMP analogues inhibited TEA transport while stimulating amantadine transport, with additive effects to insulin and bicarbonate influence.
  • Regulation of rOCT 1 and 2 was linked to transmembrane adenylyl cyclase, while amantadine transport involved soluble adenylyl cyclase.

Conclusions:

  • Intracellular cAMP microdomains play a crucial role in determining organic cation transport.
  • Soluble adenylyl cyclase, modulated by bicarbonate and lactate, influences amantadine transport, reconciling previous findings on transport affinity.
  • Findings support differential regulation of organic cation transporters, offering insights into kidney function in diabetes.

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