RT Journal Article
SR Electronic
T1 Local Anesthetics Inhibit the G Protein-Mediated Modulation of K+ and Ca++ Currents in Anterior Pituitary Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 150
OP 158
DO 10.1124/mol.55.1.150
VO 55
IS 1
A1 Zhiling Xiong
A1 Cuneyt Bukusoglu
A1 Gary R. Strichartz
YR 1999
UL http://molpharm.aspetjournals.org/content/55/1/150.abstract
AB 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.