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Am J Physiol Heart Circ Physiol (November 20, 2003). doi:10.1152/ajpheart.00549.2003
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Submitted on June 12, 2003
Accepted on November 19, 2003

The {alpha}1-AR mediated activation of NKCC in rat cardiomyocytes involves ERK dependent phosphorylation of the cotransporter

Geir Oystein Andersen1*, Tor Skomedal2, Mette Enger2, Astrid Fidjeland2, Trond Brattelid3, Finn Olav Levy3, and Jan-Bjorn Osnes2

1 Department of Pharmacology, University of Oslo, Oslo, Norway; Merck Sharpe & Dohme Cardiovascular Research Center, Rikshospitalet University Hospital, Oslo, Norway; Department of Cardiology, Ullevaal University Hospital, Oslo, Norway
2 Department of Pharmacology, University of Oslo, Oslo, Norway
3 Department of Pharmacology, University of Oslo, Oslo, Norway; Merck Sharpe & Dohme Cardiovascular Research Center, Rikshospitalet University Hospital, Oslo, Norway

* To whom correspondence should be addressed. E-mail: g.o.andersen{at}labmed.uio.no.

We studied molecular and functional characteristics as well as hormonal regulation of the Na-K-2Cl cotransporter (NKCC) in the isolated rat heart and cardiomyocytes. NKCC activity was measured as bumetanide sensitive 86Rb+ influx in isolated perfused rat hearts and isolated cardiomyocytes. Stimulation of {alpha}1-adrenoceptors (AR) by phenylephrine (30 µM) increased 86Rb+ influx. The NKCC inhibitor bumetanide (50 µM) reduced the response to phenylephrine by 45 ± 13 % (n=12, p<0.01). PD 98059 (10 µM), an inhibitor of the activation of the mitogen-activated protein kinases ERK1/2, reduced the total response to phenylephrine by 51± 13 % (n=10, p<0.01) and eliminated the bumetanide sensitive component indicating that {alpha}1- AR mediated stimulation of NKCC is dependent on activation of ERK1/2. Inhibitors of protein kinase C or phosphatidyl inositol 3-kinase had no effect. The presence of NKCC mRNA and protein was demonstrated in isolated rat cardiomyocytes. Phosphorylation of NKCC after {alpha}1-AR stimulation was shown by immunoprecipitation of the phosphoprotein from 32Pi prelabeled cardiomyocytes. Increased phosphorylation of the NKCC protein was also abolished by PD 98059. We conclude that the NKCC is present in rat cardiomyocytes and that ion transport by the cotransporter is regulated by {alpha}1-AR stimulation through phosphorylation of this protein, involving the ERK pathway.




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