Effect of erythromycin on ATP-induced intracellular calcium response in A549 cells.
ATP induced a biphasic increase in the intracellular Ca(2+)concentration ([Ca(2+)](i)), an initial spike, and a subsequent plateau in A549 cells. Erythromycin (EM) suppressed the ATP-induced [Ca(2+)](i) spike but only in the presence of extracellular calcium (Ca(2+)(o)). It was ineffective against ATP- and UTP-induced inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] formation and UTP-induced [Ca(2+)](i) spike, implying that EM perturbs Ca(2+) influx from the extracellular space rather than Ca(2+)release from intracellular Ca(2+) stores via the G protein-phospholipase C-Ins(1,4,5)P(3) pathway. A verapamil-sensitive, KCl-induced increase in [Ca(2+)](i) and the Ca(2+) influx activated by Ca(2+) store depletion were insensitive to EM. 3'-O-(4-benzoylbenzoyl)-ATP evoked an Ca(2+)(o)-dependent [Ca(2+)](i) response even in the presence of verapamil or the absence of extracellular Na(+), and this response was almost completely abolished by EM pretreatment. RT-PCR analyses revealed that P2X(4) as well as P2Y(2), P2Y(4), and P2Y(6) are coexpressed in this cell line. These results suggest that in A549 cells 1) the coexpressed P2X(4) and P2Y(2)/P2Y(4) subtypes contribute to the ATP-induced [Ca(2+)](i) spike and 2) EM selectively inhibits Ca(2+) influx through the P2X channel. This action of EM may underlie its clinical efficacy in the treatment of airway inflammation.
Zhao
D M
DM
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
Xue
H H
HH
Chida
K
K
Suda
T
T
Oki
Y
Y
Kanai
M
M
Uchida
C
C
Ichiyama
A
A
Nakamura
H
H
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004917:Erythromycin / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D009532:Nickel / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism; D058476:Receptors, Purinergic P2X2; D014407:Tumor Cells, Cultured; D014544:Uridine Triphosphate / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004963:Estrenes; C546401:P2RX2 protein, human; D020033:Protein Isoforms; D011760:Pyrrolidinones; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D004917:Erythromycin; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009532:Nickel; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D014700:Verapamil; D002118:Calcium; D014544:Uridine Triphosphate