Tamoxifen inhibition of kv7.2/kv7.3 channels

• Published in: PloS one Vol. 8; no. 9; p. e76085
• Main Authors: Ferrer, Tania, Aréchiga-Figueroa, Ivan Arael, Shapiro, Mark S, Tristani-Firouzi, Martin, Sanchez-Chapula, José A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.09.2013; Public Library of Science (PLoS)
• Subjects: Breast cancer; Channels; Cloning; Drugs; Estrogens; Excitability; HEK293 Cells; Humans; Inhibition; Inhibitory Concentration 50; KCNQ2 Potassium Channel - antagonists & inhibitors; KCNQ2 Potassium Channel - genetics; KCNQ2 Potassium Channel - metabolism; KCNQ3 Potassium Channel - antagonists & inhibitors; KCNQ3 Potassium Channel - metabolism; Kinases; Mutation; Mutation, Missense - genetics; Nervous system; Patch-Clamp Techniques; Phosphatidylinositol 4,5-diphosphate; Phosphatidylinositol 4,5-Diphosphate - metabolism; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Potassium; Potassium channels; Potassium channels (voltage-gated); Tamoxifen; Tamoxifen - pharmacology; United States > US; Utah; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0076085

KCNQ genes encode five Kv7 K(+) channel subunits (Kv7.1-Kv7.5). Four of these (Kv7.2-Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which regulates neuronal excitability. In this study, we demonstrate that tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibits Kv7.2/Kv7.3 currents heterologously expressed in human embryonic kidney HEK-293 cells. Current inhibition by tamoxifen was voltage independent but concentration-dependent. The IC50 for current inhibition was 1.68 ± 0.44 µM. The voltage-dependent activation of the channel was not modified. Tamoxifen inhibited Kv7.2 homomeric channels with a higher potency (IC50 = 0.74 ± 0.16 µM). The mutation Kv7.2 R463E increases phosphatidylinositol- 4,5-bisphosphate (PIP2) - channel interaction and diminished dramatically the inhibitory effect of tamoxifen compared with that for wild type Kv7.2. Conversely, the mutation Kv7.2 R463Q, which decreases PIP2 -channel interaction, increased tamoxifen potency. Similar results were obtained on the heteromeric Kv7.2 R463Q/Kv7.3 and Kv7.2 R463E/Kv7.3 channels, compared to Kv7.2/Kv7.3 WT. Overexpression of type 2A PI(4)P5-kinase (PIP5K 2A) significantly reduced tamoxifen inhibition of Kv7.2/Kv7.3 and Kv7.2 R463Q channels. Our results suggest that tamoxifen inhibited Kv7.2/Kv7.3 channels by interfering with PIP2-channel interaction because of its documented interaction with PIP2 and the similar effect of tamoxifen on various PIP2 sensitive channels.