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In rat hepatocytes, the hypertonic activation of Na⁺ conductance and Na⁺-K⁺-2Cl^- symport - but not Na⁺-H⁺ antiport - is mediated by protein kinase C

Heidrun Heinzinger, Frank van den Boom, Hanna Tinel and Frank Wehner

1. The initial event in the regulatory volume increase (RVI) of rat hepatocytes is an import of extracellular Na⁺ via Na⁺ conductance, Na⁺-K⁺-2Cl^- symport, and Na⁺-H⁺ antiport.
2. Here, the protein kinase inhibitors staurosporine (100 nmol l^-1) and bis-indolyl-maleimide I (400 nmol l^-1) were used to test for a possible contribution of protein kinase C (PKC) to the hypertonic activation of these transporters in confluent primary cultures.
3. Stimulation of Na⁺ conductance was monitored: (i) by use of a differential approach based on Na⁺ fluxes, (ii) by means of cable analysis, and (iii) in experiments with low Na⁺ pulses. All three experimental protocols in concert demonstrated a block of the activation of Na⁺ conductance by staurosporine and bis-indolyl-maleimide I.
4. In addition, both compounds significantly reduced the hypertonic activation of Na⁺-K⁺-2Cl^- symport (quantified on the basis of furosemide-sensitive ⁸⁶Rb⁺ uptake) to approximately 30 %.
5. In contrast, neither staurosporine nor bis-indolyl-maleimide I had any detectable effect on the hypertonicity-induced alkalinization of cell pH via Na⁺-H⁺ antiport (determined fluorometrically).
6. Staurosporine and bis-indolyl-maleimide I completely blocked the RVI of rat hepatocytes (quantified by means of confocal laser-scanning microscopy). The high efficiency of the block suggests an additional inhibitory effect of both compounds on the activity of Na⁺/K⁺-ATPase (determined as ouabain-sensitive ⁸⁶Rb⁺ uptake).
7. It is concluded that the hypertonic activation of rat hepatocyte Na⁺ conductance and Na⁺-K⁺-2Cl^- symport - but not Na⁺-H⁺ antiport - is probably mediated by PKC.

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