Desensitization of endothelin-1 binding by vasopressin via a cAMP-mediated pathway in rat CCD

F. Takemoto, S. Uchida, Hideki Katagiri, Y. Oka, A. Nakao, K. Kurokawa

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13 Citations (Scopus)

Abstract

In renal collecting ducts, endothelin-1 (ET-1) inhibits Na+ reabsorption and antagonizes the effects of arginine vasopressin (AVP). Whether AVP may affect ET-1 action in the collecting ducts that mainly express the ET(B) receptor subtype, however, remains unknown. Since ET(B), but not ET(A), possesses a consensus amino acid sequence for possible phosphorylation by protein kinase A (PKA), we hypothesized that AVP may influence ET-1 binding to the ET(B) receptor via PKA. In microdissected rat cortical collecting ducts, the specific ET-1 binding decreased by 35% (15.6 ± 4.4 vs. 24.0 ± 3.6 amol/mm in control) following 20-min preincubation with 10-7 M AVP. This decrease in ET-1 binding was mimicked by 10-5 M forskolin and by 10- 4 M dibutyryl (DB) adenosine 3',5'-cyclic monophosphate (cAMP), indicating that this heterologous desensitization may be caused by a cAMP-dependent mechanism. Moreover, N-(2{[3-(4-bromophenyl)-2-propenyl]-amino}-ethyl)-5- isoquinolinesulfonamide (H-89) and the Rp diastereoisomer of cAMP, Rp-cAMPS, which are both PKA-specific inhibitors, eliminated AVP-induced ET(B) receptor desensitization. The reduction in ET-1 binding was characterized by a decrease in binding affinity [dissociation constant (K(d)) = 4 vs. 2 nM in control] with no change in maximal binding capacity. In contrast, forskolin and DBcAMP had no effect on ET-1 binding in endothelium-denuded aortic strips, which mainly express ET(A) subtype. These results showed that AVP rapidly downregulates the ET(B) receptor by reducing K(d) through a PKA- dependent pathway. Thus ET-1 and AVP may act in a mutually antagonizing manner in the renal collecting ducts.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Fluid and Electrolyte Physiology
Volume268
Issue number3 37-3
Publication statusPublished - 1995 Jan 1
Externally publishedYes

Keywords

  • aorta
  • dibutyryladenosine 3',5'-cyclic monophosphate
  • ET(B) endothelin receptor
  • forskolin
  • H-89
  • protein kinase A
  • Rp- cAMPS

ASJC Scopus subject areas

  • Physiology

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