title: The potassium channel opener CGS7184 activates Ca²⁺ release from the endoplasmic reticulum.
abstract: CGS7184 (ethyl 1-[[(4-chlorophenyl)amino]oxo]-2-hydroxy-6-trifluoromethyl-1H-indole-3-carboxylate) is a synthetic large-conductance Ca(2+)-activated potassium (BK(Ca)) channel opener. The existing literature suggests that potassium channels are involved in cardioprotection, particularly during ischemia-reperfusion events. However, the cellular mechanisms mediating the effects of CGS7184 remain unclear. In the present study, we investigated the effect of the BK(Ca) channel opener CGS7184 on Ca(2+) homeostasis in H9C2 and C2C12 cell lines, Ca(2+) uptake by isolated sarcoplasmic reticulum (SR) vesicles, SR Ca(2+)-ATPase (SERCA) activity, and single-channel properties of the ryanodine receptor calcium release channel (RYR2) when incorporated into a planar lipid bilayer. The effects of CGS7184 on calcium homeostasis in C2C12 and H9C2 cell lines were measured with a Fura-2 fluorescent indicator. The BK(Ca) channel opener CGS7184, when added to the H9C2 and C2C12 cells, caused a concentration-dependent release of calcium from internal stores. Calcium accumulation by the SR vesicles isolated from cardiac and skeletal muscle was inhibited by CGS7184 with a half-maximal inhibition value of 0.45 ± 0.04 μM and 0.37 ± 0.03 μM, respectively. The results of the present study indicate that the BK(Ca) channel opener CGS7184 modulates cytosolic Ca(2+) concentration in H9C2 and C1C12 cells due to its interaction with the endoplasmic reticulum (ER). CGS7184 approximately doubled the opening probability of RYR2 channels; however, the compound seemed to most strongly affect channels with a higher control activity. These results strongly suggest that the BK(Ca) channel opener CGS7184 affects intracellular calcium homeostasis by interacting with the sarcoplasmic reticulum RYR2 channels.
authors: Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Pasteura 3, 02-093 Warszawa, Poland. A.Wrzosek@nencki.gov.pl
authors: Antoni
authors: A
authors: Wrzosek
authors: Zuzana
authors: Z
authors: Tomaskova
authors: Karol
authors: K
authors: Ondrias
authors: Agnieszka
authors: A
authors: Lukasiak
authors: Adam
authors: A
authors: Szewczyk
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D051379:Mice; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: C530927:CGS 7184; D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D019837:Ryanodine Receptor Calcium Release Channel; D000252:Calcium-Transporting ATPases; D002118:Calcium