Natriuretic peptide clearance receptor is transcriptionally down-regulated by β2-adrenergic stimulation in vascular smooth muscle cells

Ichiro Kishimoto, Takaaki Yoshimasa, Shin Ichi Suga, Yoshihiro Ogawa, Yasato Komatsu, Osamu Nakagawa, Hiroshi Itoh, Kazuwa Nakao

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Abstract

Three natriuretic peptide receptors (the ANP-A, ANP-B, and clearance (C) receptors) have been reported. The regulation of these receptors by catecholamines was examined in cultured rat vascular smooth muscle cells. Treatment with norepinephrine decreased the maximum 125I-ANP binding. The competitive binding assay with des[Gln18,Ser19,Gly20,Leu21,Gly22]ANP-(4-23)-NH2 (C-ANF-4-23), a specific ligand for the C receptor, revealed that the decrease in the 125I-ANP binding by norepinephrine was caused by the down-regulation of the C receptor. Isoproterenol also down-regulated the C receptor in a time- and dose-dependent manner. The catecholamine-induced down-regulation of the C receptor was antagonized by a β2-selective adrenergic antagonist, ICI 118,551 but not by an α1-, α2-, or β1-adrenergic antagonist. Forskolin, NaF and, 8-bromo-cyclic AMP also decreased the C receptor density. The isoproterenol-induced decrease in the C receptor level was further confirmed by affinity cross-linking and Western blot analysis. Northern blot analysis revealed that isoproterenol and 8-bromo-cyclic AMP decreased the steady- state level of C receptor mRNA. By contrast, neither the ANP-A receptor nor the ANP-B receptor mRNA level was affected by 8-bromo-cyclic AMP. The nuclear run-on assay showed that the transcriptional rate of the C receptor gene was decreased by isoproterenol, whereas those of the ANP-A and ANP-B receptor genes were unchanged. Isoproterenol attenuated the clearance of exogenously added ANP and augmented the ANP-stimulated intracellular cyclic GMP production to the same extent as the selective occupancy of the C receptor with C-ANF-(4-23), suggesting that the isoproterenol-induced enhancement of responsiveness to ANP could result not from the sensitization of the ANP-A or ANP-B receptor but from the down-regulation of the C receptor, which leads to the attenuated clearance of ANP. These findings suggest that the β2- adrenergic receptor stimulation down-regulates the C receptor through the decrease in the transcriptional rate of the C receptor gene and that the activation of the sympathetic nervous system augments the biological responsiveness to natriuretic peptides by attenuating their metabolic clearance in vascular walls.

Original languageEnglish
Pages (from-to)28300-28308
Number of pages9
JournalJournal of Biological Chemistry
Volume269
Issue number45
Publication statusPublished - 1994 Nov 11
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kishimoto, I., Yoshimasa, T., Suga, S. I., Ogawa, Y., Komatsu, Y., Nakagawa, O., Itoh, H., & Nakao, K. (1994). Natriuretic peptide clearance receptor is transcriptionally down-regulated by β2-adrenergic stimulation in vascular smooth muscle cells. Journal of Biological Chemistry, 269(45), 28300-28308.