Non-selective cation channel activity is required for lysophosphatidylcholine-induced monocyte migration.
Lysophosphatidylcholine (LPC) is a major atherogenic lipid which stimulates the recruitment of monocytes to atherosclerotic lesions. The physiological mechanisms underlying LPC-induced monocyte migration are poorly understood. Here we demonstrate that LPC activates non-selective cation channels, which are significantly involved in LPC-induced chemotaxis of monocytes. External LPC elicited the activation of non-selective cation currents in THP-1 monocytes, which occurred in a G protein and phospholipase C-independent manner. LPC-activated currents were almost completely inhibited by Gd(3+), La(3+), and TRAM-34. Furthermore, currents were partially reduced by either 2-aminoethoxydiphenyl borate (2-APB) or ruthenium red, while combined application of 2-APB and ruthenium red abolished LPC-activated currents. The 2-APB-sensitive current component was potentiated by flufenamic acid and Ca(2+)-free extracellular solution, while the ruthenium red-sensitive current component was abolished by capsazepine. This pharmacological profile suggests that LPC simultaneously activates TRPC6 and TRPV1 channels in monocytes. Furthermore, in the presence of Gd(3+), La(3+), TRAM-34, 2-APB, ruthenium red or capsazepine, LPC-induced chemotaxis of monocytes was substantially inhibited, indicating that activation of both channel types is required for optimal migration of LPC-stimulated monocytes. Thus, ion channel inhibition may represent a powerful strategy to attenuate the progression of atherosclerosis by reducing monocyte infiltration.
Schilling
Tom
T
Division of Basic Medical Sciences, St. George's, University of London, Cranmer Terrace, London, UK.
Eder
Claudia
C
D001896:Boron Compounds / Q000494:pharmacology; D002412:Cations / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D004963:Estrenes / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D005682:Gadolinium / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D007473:Ion Channels / Q000378:metabolism*; D007811:Lanthanum / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D012430:Ruthenium Red / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
D001896:Boron Compounds; D002412:Cations; D004963:Estrenes; D007473:Ion Channels; D008244:Lysophosphatidylcholines; D011720:Pyrazoles; D011760:Pyrrolidinones; C411671:TRAM 34; D012430:Ruthenium Red; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D007811:Lanthanum; D005682:Gadolinium; C109986:2-aminoethoxydiphenyl borate; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins