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1 Institute for Physiology II, Robert-Koch-Strasse 27b, D-48149 Münster, Germany
2 1. Department of Internal Medicine, University of Tübingen, Ottfried Müller Strasse 10, 72076 Tübingen, Germany
3 Physiological Institute, Röntgenring 9, D-97070 Würzburg, Germany
4 Physiological Institute, Medizinische Fakultät Carl-Gustav-Carus, Fetscher-Strasse 74, D-01307 Dresden, Germany
Cell migration is crucial for immune defence, wound healing or formation of tumour metastases. It has been shown that the activity of the Na+–H+ exchanger (NHE1) plays an important role in cell migration. However, so far it is unknown whether Na+– HCO3– cotransport (NBC), which has similar functions in the regulation of intracellular pH (pHi) as NHE1, is also involved in cell migration. We therefore isolated NHE-deficient Madin-Darby canine kidney (MDCK-F) cells and tested whether NBC compensates for NHE in pHi and cell volume regulation as well as in migration. Intracellular pH was measured with the fluorescent pH indicator 2'7'-bis(carboxyethyl)-5-carboxyfluorescein (BCECF). The expression of NBC isoforms was determined with semiquantitative PCR. Migration was monitored with time-lapse video microscopy and quantified as the displacement of the cell centre. We found that MDCK-F cells express the isoform NBC1 (SLCA4A gene product) at a much higher level than the isoform kNBC3 (SLCA4A8 gene product). This difference is even more pronounced in NHE-deficient cells so that NBC1 is likely to be the major acid extruder in these cells and the major mediator of propionate-induced cell volume increase. NHE-deficient MDCK-F cells migrate more slowly than normal MDCK-F cells. NBC activity promotes migration during an acute intracellular acid load and increases migratory speed and displacement on a short timescale (< 30 min) whereas it has no effect on the long-term behaviour of migrating MDCK-F cells. Taken together, our results show that NBC actvity, despite many functional similarities, does not have the same importance for cell migration as NHE1 activity.
(Received 19 June 2005;
accepted after revision 19 July 2005;
first published online 21 July 2005)
Corresponding author A. Schwab: Institute of Physiology II, Robert-Koch-Str. 27b, D-48149 Münster, Germany. Email: aschwab{at}uni-muenster.de
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