Mrp2 modulates the activity of chloride channels in... : Hepatology (original) (raw)
Original Articles: PDF Only
Mrp2 modulates the activity of chloride channels in isolated hepatocytes
1From the Departments of Physiology and Biophysics, and Internal Medicine, University of Texas Medical Branch, Galveston, TX
E-mail:[email protected]
*Address reprint requests to: Department of Physiology and Biophysics, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0641. fax: 409-772-3381.
Received January 22, 2001; Accepted April 07, 2002; previously published online December 30, 2003
Abstract
Adenosine triphosphate binding cassette family transport proteins are important organic ion transporters in hepatocytes but these molecules may also exhibit other functions. In the present study we have measured the effects of substrates of the canalicular organic ion transporter multidrug resistance associated protein 2 (Mrp2) on chloride channel activation and cell volume regulation. We found that substrates such as leukotriene D4, 17-β-estradiol glucuronide, and the leukotriene inhibitor MK-571 accelerated the activation of chloride channels by cell swelling and activated chloride channels in cytokine-pretreated hepatocytes. Two conjugated estrogens that are not Mrp2 substrates did not produce this effect. Hepatocytes derived from a strain of transport-deficient rats (TR−), which lack Mrp2 expression, showed none of these substrate effects. Coincident with their ability to activate channels, the Mrp2 substrates increased the rate of volume regulatory decrease by approximately 50% (P < .01), confirming that enhanced channel activation under this condition stimulated volume regulation. In TR-hepatocytes the Mrp2 substrate had no effect on volume regulation. In conclusion, Mrp2 plays a role in regulation of chloride channel function by reducing the lag time necessary for channel activation and consequently accelerating the process of cell volume regulation. Substrates of Mrp2 affect the ability of the protein to interact with chloride channels. These findings represent an alternative function of Mrp2 in hepatocytes.
Copyright © 2002 American Association for the Study of Liver Diseases.