Molecular pharmacology
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Molecular pharmacology · Feb 2001
Local anesthetic inhibition of G protein-coupled receptor signaling by interference with Galpha(q) protein function.
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. ⋯ 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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Molecular pharmacology · Feb 2001
Irreversible block of human heart (hH1) sodium channels by the plant alkaloid lappaconitine.
The roots from Aconitum sp. plants have long been used in Chinese herbal medicine for treating pain and various heart conditions. The principal component of Aconitum remedies is usually aconitine, a site 2 neurotoxin that may induce severe neurological symptoms and cardiovascular collapse. Some Aconitum species also contain lappaconitine, the structure of which is remarkably similar to that of aconitine. ⋯ Whereas site 2 neurotoxins often irreversibly modify channel kinetics, lappaconitine irreversibly blocks the channels. Finally, channels containing lysine substitutions within the local anesthetic receptor region at residues F1760 or N1765 are resistant to block by bupivacaine or lappaconitine. Given that site 2 neurotoxins and local anesthetics have nonidentical but overlapping binding regions, these data suggest that lappaconitine irreversibly blocks hH1 channels by binding to the site 2 receptor.