Local anesthetics inhibit receptors coupled to phosphoinositide signaling in Xenopus oocytes

Abstract

 Effects and the mechanism of action of quaternary amine local anesthetics on ligand- and voltage-activated ion currents were studied using voltage-clamped ovarian follicles and oocytes from Xenopus laevis. The fast inward and slow outward currents in response to acetylcholine were unaltered by procaine, whereas the oscillatory and smooth inward chloride currents (I _Cl) were abolished. Potassium currents (I _K) elicited by norepinephrine and oscillatory I _Cl elicited by lysophosphatidic acid were blocked. Procaine caused a noncompetitive inhibition of oscillatory I _Cl mediated by heterologously expressed neurotransmitter receptors from the rat brain. Threefold differences were found in the procaine sensitivity of the 5-HT_2a and 5-HT_2c receptors. The rank order of intrinsic inhibitory activity of local anesthetics was: procaine > lidocaine > dibucaine > tetracaine. Extra- or intracellular application of procaine did not alter the Ca²⁺-activated Cl^–current, indicating that neither the endogenous voltage-gated Ca²⁺ nor the Ca²⁺-activated Cl^–channels account for the inhibition. Procaine caused only a slight reduction in I _Cl elicited by photolysis of caged inositol 1,4,5-trisphosphate (InsP ₃) and did not abolish I _Cl triggered by GTP[γ-S]-induced direct activation of G proteins. For receptors coupling to the phosphoinositide/Ca²⁺ signal transduction pathway, the primary and physiologically relevant site of procaine action appears to be on the extracellular surface, upstream from the G protein, presumably on the receptor.