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Am J Physiol Renal Physiol (December 14, 2004). doi:10.1152/ajprenal.00300.2004
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Submitted on August 11, 2004
Accepted on December 2, 2004

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

Kamel Laghmani1, Aiji Sakamoto2, Masashi Yanagisawa3, Patricia A. Preisig1*, and Robert J. Alpern1

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

* To whom correspondence should be addressed. E-mail: Patricia.Preisig{at}UTSouthwestern.edu.

Endothelin-1 (ET-1) increases the activity of NHE3, the major proximal tubule apical membrane Na+/H+ antiporter. This effect is seen in OKP cells expressing the endothelin B (ETB) and not in cells expressing the endothelin A (ETA) receptor. However, ET-1 causes similar patterns of protein tyrosine phosphorylation, adenylyl cyclase inhibition, and increases in cell [Ca2+] in ETA and ETB expressing OKP cells, implying that an additional mechanism is required for NHE3 stimulation by the ETB receptor. The present studies used ETA and ETB 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 ETA receptor inhibits NHE3 activity, an effect for which the C-terminal tail is necessary and sufficient. ET-1 stimulation of NHE3 activity requires the C-terminal tail and the second intracellular loop of the ETB 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.




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