EndothelinB receptor activates NHE-3 by a Ca2+ -dependent pathway in OKP cells

Tzong Shinn Chu, Yan Peng, Adriana Cano, Masashi Yanagisawa, Robert J. Alpern

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

To examine the mechanisms by which endothelin (ET) regulates the Na/H antiporter isoform, NHE-3, OKP cells were stably transfected with ETA and ETB receptor cDNA. In cells overexpressing ETB, but not ETA receptors, ET-1 increased Na/H antiporter activity (JNa/H). This effect was inhibited by a nonselective endothelin receptor blocker and by a selective ETB receptor blocker but was not inhibited by an ETA selective receptor blocker. In ETB-overexpressing cells, 10-8 M ET-1 inhibited adenylyl cyclase, but protein kinase A inhibition and pertussis toxin pretreatment did not affect Na/H antiporter activation by ET-1. ET-1 caused a transient increase in cell [Ca2+], followed by a sustained increase. Increases in cell [Ca2+] were partially inhibited by pertussis toxin. ET-1-induced increases in JNa/H were 50% inhibited by clamping cell [Ca2+] low with BAPTA, and by KN62, a Ca-calmodulin kinase inhibitor. Inhibitors of protein kinase C, cyclooxygenase, lipoxygenase, and cytochrome P450 and cyclic GMP were without effect. In ETA-overexpressing cells, ET-1 increased cell [Ca2+] but did not increase JNa/H. In summary, binding of ET-1 to ETB receptors increases Na/H antiporter activity in OKP cells, an effect mediated in part by increases in cell [Ca2+] and Cacalmodulin kinase. Increases in cell [Ca2+] are not sufficient for Na/H antiporter activation.

Original languageEnglish (US)
Pages (from-to)1454-1462
Number of pages9
JournalJournal of Clinical Investigation
Volume97
Issue number6
DOIs
StatePublished - Mar 15 1996

Keywords

  • Adenylyl cyclase
  • Endothelin
  • Na/H antiporter
  • Proximal tubule

ASJC Scopus subject areas

  • Medicine(all)

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