UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Differential Free Intracellular Calcium Release by Class II Antiarrhythmics in Cancer Cell Lines

Reyes-Corral, M; Sorensen, NM; Thrasivoulou, C; Dasgupta, P; Ashmore, JF; Ahmed, A; (2019) Differential Free Intracellular Calcium Release by Class II Antiarrhythmics in Cancer Cell Lines. Journal of Pharmacology and Experimental Therapeutics 10.1124/jpet.118.254375. (In press). Green open access

[img]
Preview
Text
jpet.118.254375.1.full.pdf - Accepted version

Download (11MB) | Preview

Abstract

Class II antiarrhythmics or β-blockers are anti-sympathetic nervous system agents and act by blocking β-adrenoceptors. Despite their common clinical use, little is known about the effects of β-blockers on free intracellular calcium (Ca2+i), an important cytosolic second messenger and a key regulator of cell function. We investigated the role of four chemical analogs, commonly prescribed, β-blockers (atenolol, metoprolol, propranolol, and sotalol) on Ca2+i release and whole-cell currents in mammalian cancer cells (PC3 prostate cancer and MCF7 breast cancer cell lines). We discovered that only propranolol activated free Ca2+i release with distinct kinetics, whereas atenolol, metoprolol, and sotalol did not. The propranolol-induced Ca2+i release was significantly inhibited by the chelation of extracellular calcium with ethylene glycol tetraacetic acid (EGTA) and by dantrolene, an inhibitor of the endoplasmic reticulum ryanodine receptor channels, and it was completely abolished by 2- aminoethoxydiphenyl borate, an inhibitor of the endoplasmic reticulum inositol-1,4,5- trisphosphate (IP3) receptor channels. Exhaustion of endoplasmic reticulum stores with 4- chloro-m-cresol, a ryanodine receptor activator, or thapsigargin, a sarco/endoplasmic reticulum Ca2+ ATPase inhibitor, precluded the propranolol-induced Ca2+i release. Finally, pre-incubation of cells with sotalol or timolol, non-selective blockers of β-adrenoceptors, also reduced the Ca2+i release activated by propranolol. Our results show that different β-blockers have differential effects on whole-cell currents and free Ca2+i release and that propranolol activates store-operated Ca2+i release via a mechanism that involves calcium-induced calcium release and putative downstream transducers such as IP3 The differential action of class II antiarrhythmics on Ca2+i release may have implications on the pharmacology of these drugs.

Type: Article
Title: Differential Free Intracellular Calcium Release by Class II Antiarrhythmics in Cancer Cell Lines
Open access status: An open access version is available from UCL Discovery
DOI: 10.1124/jpet.118.254375
Publisher version: https://doi.org/10.1124/jpet.118.254375
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Ca imaging, antiarrhythmic drugs, calcium signaling, cancer, electrophysiology
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10066955
Downloads since deposit
1Download
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item