TY - JOUR T1 - Local Anesthetics Inhibit the G Protein-Mediated Modulation of K<sup>+</sup> and Ca<sup>++</sup> Currents in Anterior Pituitary Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 150 LP - 158 DO - 10.1124/mol.55.1.150 VL - 55 IS - 1 AU - Zhiling Xiong AU - Cuneyt Bukusoglu AU - Gary R. Strichartz Y1 - 1999/01/01 UR - http://molpharm.aspetjournals.org/content/55/1/150.abstract N2 - The effects of local anesthetics (LAs) on G protein-mediated responses of voltage-dependent K+ (I K) and Ca++ currents in rat anterior pituitary tumor (GH3) cells were analyzed by using a whole-cell voltage clamp. Extracellular lidocaine inhibitedI K with an IC50 of 1.9 mM, comparable to 2.6 mM for I Ba but 10 times higher than the IC50 forI Na (0.17 mM). Low concentrations of lidocaine (30–100 μM), which had no direct effect on basalI K, attenuated both the stimulatory and inhibitory modulation of K+ channels by thyrotropin-releasing hormone (TRH). Both modulations had an IC50 ∼40 μM independent of [TRH]. Intracellular QX314 (100 μM), a quaternary, charged form of lidocaine, also significantly attenuated the TRH effects; however, external QX314 and the neutral LA benzocaine (100 μM) did not. Lidocaine (≤100 μM) inhibited the TRH-induced increase in [Ca++] but failed to block either the GTP-γ-S-induced increase in I K, the activation ofI K by directly elevated [Ca++] (ca. 3 × 10−7 M), or the phorbol-12,13-dibutyrate-induced inhibition of Ca++-activated I K. Agonist binding assays revealed that none of the these LAs affected TRH receptor binding. Similar to its effect on TRH modulation ofI K, lidocaine (100 μM) attenuated the inhibition of Ca++ channels in GH3 cells by somatostatin (1 μM). These results suggest that lidocaine’s action occurs between agonist binding and G protein activation. Such inhibition of G protein pathways may be an important component of the general action of LAs acting at spinal sites, or for i.v. therapeutics or during cardiotoxic episodes. ER -