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Tamoxifen inhibits inward rectifier K+ 2.x family of inward rectifier channels by interfering with phosphatidylinositol 4,5-bisphosphate-channel interactions.
J Pharmacol Exp Ther. 2009 Nov; 331(2):563-73.JP

Abstract

Tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibits the inward rectifier potassium current (I(K1)) in cardiac myocytes by an unknown mechanism. We characterized the inhibitory effects of tamoxifen on Kir2.1, Kir2.2, and Kir2.3 potassium channels that underlie cardiac I(K1). We also studied the effects of 4-hydroxytamoxifen and raloxifene. All three drugs inhibited inward rectifier K(+) 2.x (Kir2.x) family members. The order of inhibition for all three drugs was Kir2.3 > Kir2.1 approximately Kir2.2. The onset of inhibition of Kir2.x current by these compounds was slow (T(1/2) approximately 6 min) and only partially recovered after washout (approximately 30%). Kir2.x inhibition was concentration-dependent but voltage-independent. The time course and degree of inhibition was independent of external or internal drug application. We tested the hypothesis that tamoxifen interferes with the interaction between the channel and the membrane-delimited channel activator, phosphatidylinositol 4,5-bisphosphate (PIP(2)). Inhibition of Kir2.3 currents was significantly reduced by a single point mutation of I213L, which enhances Kir2.3 interaction with membrane PIP(2). Pretreatment with PIP(2) significantly decreased the inhibition induced by tamoxifen, 4-hydroxytamoxifen, and raloxifene on Kir2.3 channels. Pretreatment with spermine (100 microM) decreased the inhibitory effect of tamoxifen on Kir2.1, probably by strengthening the channel's interaction with PIP(2). In cat atrial and ventricular myocytes, 3 microM tamoxifen inhibited I(K1), but the effect was greater in the former than the latter. The data strongly suggest that tamoxifen, its metabolite, and the estrogen receptor inhibitor raloxifene inhibit Kir2.x channels indirectly by interfering with the interaction between the channel and PIP(2).

Authors+Show Affiliations

Unidad de Investigación Carlos Méndez del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Colima, México.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19654266

Citation

Ponce-Balbuena, Daniela, et al. "Tamoxifen Inhibits Inward Rectifier K+ 2.x Family of Inward Rectifier Channels By Interfering With Phosphatidylinositol 4,5-bisphosphate-channel Interactions." The Journal of Pharmacology and Experimental Therapeutics, vol. 331, no. 2, 2009, pp. 563-73.
Ponce-Balbuena D, López-Izquierdo A, Ferrer T, et al. Tamoxifen inhibits inward rectifier K+ 2.x family of inward rectifier channels by interfering with phosphatidylinositol 4,5-bisphosphate-channel interactions. J Pharmacol Exp Ther. 2009;331(2):563-73.
Ponce-Balbuena, D., López-Izquierdo, A., Ferrer, T., Rodríguez-Menchaca, A. A., Aréchiga-Figueroa, I. A., & Sánchez-Chapula, J. A. (2009). Tamoxifen inhibits inward rectifier K+ 2.x family of inward rectifier channels by interfering with phosphatidylinositol 4,5-bisphosphate-channel interactions. The Journal of Pharmacology and Experimental Therapeutics, 331(2), 563-73. https://doi.org/10.1124/jpet.109.156075
Ponce-Balbuena D, et al. Tamoxifen Inhibits Inward Rectifier K+ 2.x Family of Inward Rectifier Channels By Interfering With Phosphatidylinositol 4,5-bisphosphate-channel Interactions. J Pharmacol Exp Ther. 2009;331(2):563-73. PubMed PMID: 19654266.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tamoxifen inhibits inward rectifier K+ 2.x family of inward rectifier channels by interfering with phosphatidylinositol 4,5-bisphosphate-channel interactions. AU - Ponce-Balbuena,Daniela, AU - López-Izquierdo,Angélica, AU - Ferrer,Tania, AU - Rodríguez-Menchaca,Aldo A, AU - Aréchiga-Figueroa,Iván A, AU - Sánchez-Chapula,José A, Y1 - 2009/08/04/ PY - 2009/8/6/entrez PY - 2009/8/6/pubmed PY - 2009/12/16/medline SP - 563 EP - 73 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 331 IS - 2 N2 - Tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibits the inward rectifier potassium current (I(K1)) in cardiac myocytes by an unknown mechanism. We characterized the inhibitory effects of tamoxifen on Kir2.1, Kir2.2, and Kir2.3 potassium channels that underlie cardiac I(K1). We also studied the effects of 4-hydroxytamoxifen and raloxifene. All three drugs inhibited inward rectifier K(+) 2.x (Kir2.x) family members. The order of inhibition for all three drugs was Kir2.3 > Kir2.1 approximately Kir2.2. The onset of inhibition of Kir2.x current by these compounds was slow (T(1/2) approximately 6 min) and only partially recovered after washout (approximately 30%). Kir2.x inhibition was concentration-dependent but voltage-independent. The time course and degree of inhibition was independent of external or internal drug application. We tested the hypothesis that tamoxifen interferes with the interaction between the channel and the membrane-delimited channel activator, phosphatidylinositol 4,5-bisphosphate (PIP(2)). Inhibition of Kir2.3 currents was significantly reduced by a single point mutation of I213L, which enhances Kir2.3 interaction with membrane PIP(2). Pretreatment with PIP(2) significantly decreased the inhibition induced by tamoxifen, 4-hydroxytamoxifen, and raloxifene on Kir2.3 channels. Pretreatment with spermine (100 microM) decreased the inhibitory effect of tamoxifen on Kir2.1, probably by strengthening the channel's interaction with PIP(2). In cat atrial and ventricular myocytes, 3 microM tamoxifen inhibited I(K1), but the effect was greater in the former than the latter. The data strongly suggest that tamoxifen, its metabolite, and the estrogen receptor inhibitor raloxifene inhibit Kir2.x channels indirectly by interfering with the interaction between the channel and PIP(2). SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/19654266/Tamoxifen_inhibits_inward_rectifier_K+_2_x_family_of_inward_rectifier_channels_by_interfering_with_phosphatidylinositol_45_bisphosphate_channel_interactions_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=19654266 DB - PRIME DP - Unbound Medicine ER -