LU52396, AN INHIBITOR OF THE STORE-DEPENDENT (CAPACITATIVE) CA2+ INFLUX

The effects of phenyl)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 d erived from the cerebellum and the skeletal muscle. LU52396 was found to be a potent inhibitor (K-i of about 2 mu M) of the Ca2+ influx acti vated by depletion of intracellular Ca2+ stores, a phenomenon referred to as store-dependent or capacitative Ca2+ influx. Such an effect, wh ich was reversed by cell washing, was mediated neither by a depolariza tion 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 th e plasma membrane or, less likely, on its regulatory mechanisms. Addit ional effects, i.e. inhibition of receptor-mediated Ca2+ influx, of Ca 2+ release from intracellular stores via either inositol 1,4,5-trispho sphate or ryanodine receptors, and of Ca2+ reuptake into the stores vi a sarcoplasmic-endoplasmic reticulum Ca2+-ATPases, were also induced b y the drug, however at concentrations 20-fold or more than those effec tive on the store-dependent influx. To our knowledge LU52396 is the fi rst pharmacological tool that is found to be addressed with some prefe rence to the store-dependent Ca2+ influx. It promises, threfore, to be useful for the characterization of the process, the identification of the responsible channels and, possibly, also of the molecular mechani sms through which these channels operate.