Block by fluoxetine of volume‐regulated anion channels

Abstract

1 We have used the whole-cell patch clamp technique to study the e ect of¯uoxetine, a commonly used antidepressant drug, on the volume-regulated anion channel (VRAC) in calf pulmonary artery endothelial (CPAE) cells. We also examined its e ects on other Cl 7 channels, i.e. the Ca 2+ -activated Cl 7 current (I Cl,Ca ) and the cystic ®brosis transmembrane conductance regulator (CFTR) to assess the speci®city of this compound for VRAC. 2 At pH 7.4¯uoxetine induced a fast and reversible block of the volume-sensitive chloride current (I Cl,swell ), with a K i value of 6.0+0.5 mM (n=6-9). The blocking e ciency increased with increasing extracellular pH (K i =0.32+0.01 mM at pH 8.8, n=3-9), indicating that the blockade is mediated by the uncharged form of¯uoxetine. 3 Fluoxetine inhibited Ca 2+ -activated Cl 7 currents, I Cl,Ca , activated by loading CPAE cells via the patch pipette with 1000 nM free Ca 2+ (K i =10.7+1.6 mM at pH 7.4, n=3-5). The CFTR channel, transiently transfected in CPAE cells, was also inhibited with a K i value of 26.9+9.4 mM at pH 7.4 (n=3). 4 This study describes for the ®rst time the e ects of¯uoxetine on anion channels. Our data reveal a potent block of VRAC at¯uoxetine concentrations close to plasma concentrations. The results suggest a hydrophobic interaction with high a nity between uncharged¯uoxetine and volumeactivated chloride channels. Ca 2+ -activated Cl 7 currents and CFTR are also blocked by¯uoxetine, revealing a novel characteristic of the drug as a chloride channel modulator.

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Various Antidepressant Drugs

“…In contrast, the interaction of antidepressants with muscarinic, a 1 adrenergic, and H 1 histamine receptors is involved in some of the adverse side effects (Baldessarini, 2001). It has also been shown that antidepressants inhibit the functions of several other receptors and ion channels, such as 5-HT 2C (Ni and Miledi, 1997) and 5-HT 3 receptors (Fan, 1994), nicotinic acetylcholine receptors (García-Colunga et al, 1997;Maggi et al, 1998), N-methyl-D-aspartate (NMDA) receptor channels (Sernagor et al, 1989), P2X 2 receptors (Nakazawa et al, 1999), voltage-gated Ca 2 þ , Na þ , and K þ channels (Ogata et al, 1989;Mathie et al, 1998;Pancrazio et al, 1998;Teschemacher et al, 1999;Yeung et al, 1999;Deák et al, 2000;Choi et al, 2001;Cuellar-Quintero et al, 2001), Ca 2 þ -activated K þ channels (Kamatchi and Ticku, 1991;Lee et al, 1997;Dreixler et al, 2000;Terstappen et al, 2001), and Cl À channels (Maertens et al, 1999(Maertens et al, , 2002. The effects might also be involved in the molecular and cellular mechanisms underlying some of the therapeutic effects and side effects of various antidepressants.…”

Development and Validation of Fluorescence-Based and Automated Patch Clamp–Based Functional Assays for the Inward Rectifier Potassium Channel Kir4.1

“…1C, D), consistent with reports that the drug inhibits other ion channels. [30][31][32] Thus, overnight induction with tetracycline gives rise to robust, fluoxetineinhibitable Kir4.1 channel activity in this stable cell line. As shown in Figure 1E, Western blot analysis revealed that overnight incubation with tetracycline led to the dose-dependent induction of Kir4.1 channel expression that reached a maximum level with 0.1 mg/mL tetracycline.…”

Open Channel Block of Kv3.1 Currents by Fluoxetine

“…For example, it has been reported that fluoxetine is a potent blocker of voltage-gated Ca 2+ channels (2), Na + channels (3), and K + channels (4 -7) at concentrations between 1 and 100 µM. In addition, anion channels (8) and nicotinic acetylcholine receptors (9) are also blocked.…”