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Aminoglycoside antibiotics induce pH-sensitive activation of the calcium-sensing receptor.

Abstract：

:The aminoglycoside antibiotic (AGA) neomycin is a known agonist of the extracellular calcium-sensing receptor (CaR). To test whether other AGA drugs stimulate the CaR, we studied the relative effects of four AGAs on intracellular Ca(2+) concentration ([Ca(2+)](i)) using CaR-transfected human embryonic kidney (HEK)-293 cells. Gentamicin, tobramycin, and neomycin evoked dose-dependent increases in [Ca(2+)](i) with EC(50) values of 258, 177, and 43 microM, respectively, in CaR-transfected, but not in non-transfected cells. Kanamycin was ineffective at doses <1mM. Thus, AGAs stimulate the CaR with a rank order of potency that correlates positively with the number of their attached amino groups. The CaR is expressed on the apical surface of renal proximal tubule cells, which is also the site of AGA endocytosis and nephrotoxicity. In the current study, reducing extracellular pH from 7.4 to 6.9, to mimic the luminal pH of the proximal tubule, enhanced the sensitivity of the CaR to tobramycin, suggesting that the AGAs may be more potent CaR agonists in the proximal tubule than elsewhere. This pH effect was not observed when stimulating CaR with the non-ionizable agonist, Gd(3+), suggesting that the enhanced AGA effect is due to increased ionization of the drug. Thus, we show that a number of AGA drugs are capable of CaR activation and that their potency most likely relates to the number of their amino side chains and to their pH-dependent charge characteristics. The contribution of CaR activation to the pharmacological/toxicological effects of these AGAs remains to be determined.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

McLarnon S,Holden D,Ward D,Jones M,Elliott A,Riccardi D

doi

10.1016/s0006-291x(02)02133-2

subject

Has Abstract

pub_date

2002-09-13 00:00:00

pages

71-7

issue

1

eissn

0006-291X

issn

1090-2104

pii

S0006291X02021332

journal_volume

297

pub_type

杂志文章

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