title: Pharmacological evidence for Orai channel activation as a source of cardiac abnormal automaticity.
abstract: Calcium transport through plasma membrane voltage-independent calcium channels is vital for signaling events in non-excitable and excitable cells. Following up on our earlier work, we tested the hypothesis that this type of calcium transport can disrupt myocardial electromechanical stability. Our Western and immunofluorescence analyses show that left atrial and ventricular myocytes express the Orai1 and the Orai3 calcium channels. Adding the Orai activator 2-aminoethoxydiphenyl borate (2-APB) to the superfusate of rat left atria causes these non-automatic muscles to contract spontaneously and persistently at rates of up to 10 Hz, and to produce normal action potentials from normal resting potentials, all in the absence of external stimulation. 2-APB likewise induces such automatic activity in superfused rat left ventricular papillary muscles, and the EC(50)s at which 2-APB induces this activity in both muscles are similar to the concentrations which activate Orais. Importantly, the voltage-independent calcium channel inhibitor 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF-96365) suppresses this automaticity with an IC(50) of 11 ± 0.6 μM in left atria and 6 ± 1.6 μM in papillary muscles. 1-(5-Iodonaphthalene-1-sulfonyl)-hexahydro-1,4-diazepine (ML-7), a second voltage-independent calcium channel inhibitor, and two calmodulin inhibitors also prevent 2-APB automaticity while two calmodulin-dependent protein kinase II inhibitors do not. Thus an activator of the Orai calcium channels provokes a novel type of high frequency automaticity in non-automatic heart muscle.
authors: Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. wolk@uab.edu
authors: Paul E
authors: PE
authors: Wolkowicz
authors: Jian
authors: J
authors: Huang
authors: Patrick K
authors: PK
authors: Umeda
authors: Oleg F
authors: OF
authors: Sharifov
authors: Edlue
authors: E
authors: Tabengwa
authors: Brian A
authors: BA
authors: Halloran
authors: Ferdinand
authors: F
authors: Urthaler
authors: Hernan E
authors: HE
authors: Grenett
mesh_terms: D000818:Animals; D016279:Atrial Function, Left / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D001896:Boron Compounds / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D000071740:ORAI1 Protein; D051381:Rats
chemical_list: D001381:Azepines; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002147:Calmodulin; D007093:Imidazoles; D009281:Naphthalenes; D000071740:ORAI1 Protein; C532493:Orai1 protein, rat; C070571:ML 7; C109986:2-aminoethoxydiphenyl borate; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole