Local Anesthetic Inhibition of G Protein-Coupled Receptor Signaling by Interference with Gαq Protein Function
- Department of Anesthesiology and Pain Management, University Hospital Maastricht, The Netherlands, and 1University of Virginia, Charlottesville, Virginia (M.W.H., K.S.W., A.B., M.E.D.); and2Department of Anesthesiology, University of Heidelberg, Germany (M.W.H., K.S.W., A.B.)
Abstract
Although local anesthetics are considered primarily Na+ channel blockers, previous studies suggest a common intracellular site of action on different G protein-coupled receptors. In the present study, we characterized this site for the LPA, m1 muscarinic, and trypsin receptor. Xenopus laevis oocytes expressing endogenous LPA and trypsin or recombinant m1 receptors were two-electrode voltage clamped. We studied LPA inhibition in the presence of ropivacaine stereoisomers to determine whether LA act on a protein site. Ropivacaine inhibited LPA signaling in a stereoselective and noncompetitive manner, suggesting a protein interaction. Antisense injection was used to characterize G protein α-subunits involved in mediation of LPA, m1, trypsin, and angiotensin1A receptor signaling. Lidocaine and its analog QX314 were injected into oocytes expressing these receptors to examine a potential role for specific G protein α-subunits as targets for LA. Gαq was shown to be among the primary G protein subunits mediating the LPA, m1, and trypsin receptor signaling, all of which were inhibited to a similar degree by intracellular injected QX314 (424 × 10−6M). Since the angiotensin1A receptor, previously shown not to be affected by LA, was found not to signal via Gαq, but via Gαo and Gα14, the intracellular effect of LA most likely takes place at the Gαq-subunit.
Footnotes
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Send reprint requests to: Marcel E. Durieux, M.D., Ph.D., Dept. of Anesthesiology and Pain Management, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail:durieux{at}virginia.edu
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This work was supported by National Institutes of Health Grant GMS 52387 and an American Heart Association grant, Mid-Atlantic Affiliate VHA 9920345U. M.W.H. is supported in part by the Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany and by a grant from the German Research Society (DFG HO 2199/1–1), Bonn, Germany. Supported in part by the 2000 Ben Covino Research Award to M.W.H., sponsored by AstraZeneca Pain Control, Sweden.
- Abbreviations:
- LA
- local anesthetics
- LPA
- lysophosphatidic acid
- MCh
- acetyl-β-methylcholine bromide
- AT
- angiotensin
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- Received July 12, 2000.
- Accepted November 16, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
