LU52396, an inhibitor of the store-dependent (capacitative) Ca2+ influx.
The effects of 1-[2-(4-fluorophenyl)cyclohexyl]-2-[4-(3-phenylalkyl)-piperazin -1-yl]- ethanol, LU52396, on a) Ca2+ influx across the plasma membrane and b) Ca2+ mobilization from intracellular rapidly-exchanging Ca2+ stores were investigated in HeLa cells and in isolated microsomal fractions derived from the cerebellum and the skeletal muscle. LU52396 was found to be a potent inhibitor (Ki of about 2 microM) of the Ca2+ influx activated by depletion of intracellular Ca2+ stores, a phenomenon referred to as store-dependent or capacitative Ca2+ influx. Such an effect, which was reversed by cell washing, was mediated neither by a depolarization of the cell, with decrease in the driving force for cation influx, nor by a change of the intracellular pH, and might therefore be due to a direct action of the drug on either the responsible channel in the plasma membrane or, less likely, on its regulatory mechanisms. Additional effects, i.e. inhibition of receptor-mediated Ca2+ influx, of Ca2+ release from intracellular stores via either inositol 1,4,5-trisphosphate or ryanodine receptors, and of Ca2+ reuptake into the stores via sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPases, were also induced by the drug, however at concentrations 20-fold or more than those effective on the store-dependent influx. To our knowledge LU52396 is the first pharmacological tool that is found to be addressed with some preference to the store-dependent Ca2+ influx. It promises, therefore, to be useful for the characterization of the process, the identification of the responsible channel and, possibly, also of the molecular mechanisms through which these channels operate.
Clementi
E
E
Chair of Pharmacology, Faculty of Pharmacy, University of Reggio Calabria, Catanzaro, Italy.
Martini
A
A
Stefani
G
G
Meldolesi
J
J
Volpe
P
P
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002645:Chickens; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D015290:Second Messenger Systems / Q000187:drug effects
D015220:Calcium Channels; C094080:LU 52396; D010879:Piperazines; D000252:Calcium-Transporting ATPases; D002118:Calcium