@entity4028 antibiotics induce pH-sensitive activation of the XXXX -sensing receptor.

@entity1 @entity801 @entity1472 @entity2890 @entity7913 @entity15311 @entity5154 @entity460 @entity141 @entity4028
The @entity4028 antibiotic (AGA) neomycin is a known agonist of the extracellular @entity460 -sensing receptor (CaR). To test whether other AGA drugs stimulate the CaR, we studied the relative effects of four AGAs on intracellular @entity141 concentration ([ @entity141 ](i)) using CaR-transfected @entity1 embryonic kidney (HEK)-293 cells. @entity801 , @entity2890 , and @entity5154 evoked dose-dependent increases in [ @entity141 ](i) with EC(50) values of 258, 177, and 43 microM, respectively, in CaR-transfected, but not in non-transfected cells. @entity7913 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 @entity1472 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 @entity2890 , 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, @entity15311 , 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 @entity1472 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.
