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This Article Full Text Full Text (PDF) All Versions of this Article: 288/4/F732    most recent 00300.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Laghmani, K. Articles by Alpern, R. J. Search for Related Content PubMed PubMed Citation Articles by Laghmani, K. Articles by Alpern, R. J.

A consensus sequence in the endothelin-B receptor second intracellular loop is required for NHE3 activation by endothelin-1

¹Department of Internal Medicine and the ³Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas; and ²Division of Biotechnology and Department of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan

Submitted 11 August 2004 ; accepted in final form 2 December 2004

Endothelin-1 (ET-1) increases the activity of Na⁺/H⁺ exchanger 3 (NHE3), the major proximal tubule apical membrane Na⁺/H⁺ antiporter. This effect is seen in opossum kidney (OKP) cells expressing the endothelin-B (ET_B) and not in cells expressing the endothelin-A (ET_A) receptor. However, ET-1 causes similar patterns of protein tyrosine phosphorylation, adenylyl cyclase inhibition, and increases in cell [Ca²⁺] in ET_A- and ET_B-expressing OKP cells, implying that an additional mechanism is required for NHE3 stimulation by the ET_B receptor. The present studies used ET_A and ET_B receptor chimeras and site-directed mutagenesis to identify the ET receptor domains that mediate ET-1 regulation of NHE3 activity. We found that binding of ET-1 to the ET_A receptor inhibits NHE3 activity, an effect for which the COOH-terminal tail is necessary and sufficient. ET-1 stimulation of NHE3 activity requires the COOH-terminal tail and the second intracellular loop of the ET_B receptor. Within the second intracellular loop, a consensus sequence was identified, KXXXVPKXXXV, that is required for ET-1 stimulation of NHE3 activity. This sequence suggests binding of a homodimeric protein that mediates NHE3 stimulation.

opossum kidney cells; endothelin-A/endothelin-B chimeras; sodium/hydrogen antiporter activity

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