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Vol. 59, Issue 2, 294-301, February 2001

Local Anesthetic Inhibition of G Protein-Coupled Receptor Signaling by Interference with Galpha q Protein Function

Markus W. Hollmann, Kathrin S. Wieczorek, Andreas Berger, and Marcel E. Durieux

Department of Anesthesiology and Pain Management, University Hospital Maastricht, The Netherlands, and University of Virginia, Charlottesville, Virginia (M.W.H., K.S.W., A.B., M.E.D.); and Department of Anesthesiology, University of Heidelberg, Germany (M.W.H., K.S.W., A.B.)

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 alpha -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 alpha -subunits as targets for LA. Galpha q 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 × 10-6 M). Since the angiotensin1A receptor, previously shown not to be affected by LA, was found not to signal via Galpha q, but via Galpha o and Galpha 14, the intracellular effect of LA most likely takes place at the Galpha q-subunit.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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