TY - JOUR
T1 - LU52396, an inhibitor of the store-dependent (capacitative) Ca2+ influx
AU - Clementi, Emilio
AU - Martini, Adelina
AU - Stefani, Giulia
AU - Meldolesi, Jacopo
AU - Volpe, Pompeo
PY - 1995/3/15
Y1 - 1995/3/15
N2 - The effects of 1-[2-(4-fluorophenyl)cyclohexyl]-2-[4-(3-phenylalkyl)-piperazin-1-yl]-et hanol, 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 μM) 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 Ca2+ reuptake into the stores via sarcoplasmic-endoplasmic reticulum Ca2+-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 channels and, possibly, also of the molecular mechanisms through which these channels operate.
AB - The effects of 1-[2-(4-fluorophenyl)cyclohexyl]-2-[4-(3-phenylalkyl)-piperazin-1-yl]-et hanol, 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 μM) 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 Ca2+ reuptake into the stores via sarcoplasmic-endoplasmic reticulum Ca2+-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 channels and, possibly, also of the molecular mechanisms through which these channels operate.
KW - Ca ATPase
KW - Ca influx, store-dependent
KW - Ca store
KW - IP receptor
KW - Ryanodine receptor
KW - Second messenger-operated channel
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U2 - 10.1016/0922-4106(95)90164-7
DO - 10.1016/0922-4106(95)90164-7
M3 - Article
C2 - 7781709
AN - SCOPUS:0028952555
VL - 289
SP - 23
EP - 31
JO - European Journal of Pharmacology - Molecular Pharmacology Section
JF - European Journal of Pharmacology - Molecular Pharmacology Section
SN - 0922-4106
IS - 1
ER -