Interactions between propofol and lipid mediator receptors: inhibition of lysophosphatidate signaling.
As a highly lipophilic drug, propofol may interact with lipophilic domains in addition to its likely primary site of action on the gamma-aminobutyrateA) (GABA(A)) receptor. Likely candidates for such interaction are the G protein-coupled membrane receptors for lipid intercellular mediators. The phospholipid lysophosphatidate (LP) has attracted attention as such a signaling molecule. It has a variety of biological actions, including vasoconstriction. We therefore studied the interaction between propofol and the LP receptor. Intracellular Ca2+ release in response to LP was assessed by measuring C1- flux through Ca(2+)-activated C1- channels in Xenopus oocytes. The average charge movement in response to LP 10(-7)M was 2.0 +/- 0.2 microCoulombs. Propofol in Intralipid (0.01%) dose-dependently inhibited LP signaling (50% inhibitory concentration [IC50] 5.38 microM). Propofol 28 microM inhibited LP signaling by 81%. Intralipid (0.01%) was without effect. To ascertain that intracellular signaling pathways and the Ca(2+)-activated C1- channel were not affected by propofol, we tested the effects of propofol (5.6 microM) on currents induced by methylcholine (10(-7)M) in oocytes expressing the m1 muscarinic acetylcholine receptor. No inhibition was observed. As both receptors share the same intracellular signaling pathway, we conclude that clinically relevant concentrations of propofol most likely inhibit the LP receptor or its G protein. Inhibition of LP signaling may explain some of propofol's vasodilating actions.
Department of Anesthesiology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
M A
MA
Rossi
C K
CK
Chan
J D
JD
Christensen
E J
EJ
DeGuzman
M E
ME
Durieux
D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics; D018118:Chloride Channels / Q000187:drug effects; D002794:Choline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D058787:GABA-A Receptor Antagonists; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D008246:Lysophospholipids / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D011976:Receptors, Muscarinic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014982:Xenopus laevis
D018686:Anesthetics, Intravenous; D018118:Chloride Channels; D005217:Fat Emulsions, Intravenous; D058787:GABA-A Receptor Antagonists; D008246:Lysophospholipids; D018727:Muscarinic Antagonists; D011956:Receptors, Cell Surface; D011976:Receptors, Muscarinic; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C017506:methylcholine; D019204:GTP-Binding Proteins; D002794:Choline; D002118:Calcium; D015742:Propofol