Mol Pharmacol 2001 Feb 01;592:294-301. doi: 10.1124/mol.59.2.294.

Local anesthetic inhibition of G protein-coupled receptor signaling by interference with Galpha(q) protein function.

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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 angiotensin(1A) 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 x 10(-6) M). Since the angiotensin(1A) 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.

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Species referenced: Xenopus laevis
Genes referenced: prss1 suclg1