INTERACTIONS BETWEEN PROPOFOL AND LIPID MEDIATOR RECEPTORS - INHIBITION OF LYSOPHOSPHATIDATE SIGNALING

As a highly lipophilic drug, propofol may interact with lipophilic dom ains in addition to its likely primary site of action on the gamma-ami nobutyrate(A) (GABA(A)) receptor. Likely candidates for such interacti on are the G protein-coupled membrane receptors for lipid intercellula r mediators. The phospholipid lysophosphatidate (LP) has attracted att ention as such a signaling molecule. It has a variety of biological ac tions, including vasoconstriction. We therefore studied the interactio n between propofol and the LP receptor. Intracellular Ca2+ release in response to LP was assessed by measuring Cl- flux through Ca2+ activat ed Cl- channels in Xenopus oocytes. The average charge movement in res ponse to LP 10(-7) M was 2.0 +/- 0.2 microCoulombs. Propofol in Intral ipid(R) (0.01%) dose-dependently inhibited LP signaling (50% inhibitor y concentration [IC50] 5.38 mu M). Propofol 28 mu M inhibited LP signa ling by 81%. Intralipid(R) (0.01%) was without effect. To ascertain th at intracellular signaling pathways and the Ca2+- activated Cl- channe l were not affected by propofol, we tested the effects of propofol (5. 6 mu M) On currents induced by methylcholine (10(-7) M) in oocytes exp ressing the mi muscarinic acetylcholine receptor. No inhibition was ob served. As both receptors share the same intracellular signaling pathw ay, we conclude that clinically relevant concentrations of propofol mo st likely inhibit the LP receptor or its G protein. Inhibition of LP s ignaling may explain some of propofol's vasodilating actions.