LOCAL-ANESTHETICS INHIBIT RECEPTORS COUPLED TO PHOSPHOINOSITIDE SIGNALING IN XENOPUS OOCYTES

Effects and the mechanism of action of quaternary amine local anesthet ics on ligand- and voltage-activated ion currents were studied using v oltage-clamped ovarian follicles and oocytes from Xenopus laevis. The fast inward and slow outward currents in response to acetylcholine wer e unaltered by procaine, whereas the oscillatory and smooth inward chl oride currents (I-Cl) were abolished. Potassium currents (I-K) elicite d by norepinephrine and oscillatory I-Cl elicited by lysophosphatidic acid were blocked. Procaine caused a noncompetitive inhibition of osci llatory I-Cl mediated by heterologously expressed neurotransmitter rec eptors from the rat brain. Threefold differences were found in the pro caine sensitivity of the 5-HT2a and 5-HT2c receptors. The rank order o f intrinsic inhibitory activity of local anesthetics was: procaine > l idocaine, dibucaine > tetracaine. Extra- or intracellular application of procaine did not alter the Ca2+-activated Cl- current, indicating t hat neither the endogenous voltage-gated Ca2+ nor the Ca2+-activated C l- channels account for the inhibition. Procaine caused only a slight reduction in I-Cl elicited by photolysis of caged inositol 1,4,5-trisp hosphate (InsP(3)) and did not abolish I-Cl triggered by GTP[gamma-S]- induced direct activation of G proteins. For receptors coupling to the phosphoinositide/Ca2+ signal transduction pathway the primary and phy siologically relevant site of procaine action appears to be on the ext racellular surface, upstream from the G protein. presumably on the rec eptor.