title: Highly supralinear feedback inhibition of Ca2+ uptake by the Ca2+ load of intracellular stores.
abstract: Net Ca2+ uptake into intracellular Ca2+ stores of homogenized cells is transient, even when the extravesicular Ca2+ concentration is kept constant. To study the mechanism underlying the phenomenon, we have investigated 45Ca2+ uptake by HL-60 cell homogenates. The initial rate of Ca2+ uptake as well as the final amount of stored Ca2+ were a function of the extravesicular Ca2+ concentration. However, Ca2+ uptake stopped independently of the extravesicular Ca2+ concentration after approximately 10 min. Studies using Ca2+-ATPase inhibitors demonstrated that the transient nature of the net uptake was not due to Ca2+ efflux. Monovalent cation ionophores did not influence the Ca2+ uptake curves, excluding a relevant involvement of pH and membrane potential. Together with the observation of a continued Ca2+ uptake in the presence of the intralumenal Ca2+ chelator oxalate, these results strongly suggest a feedback inhibition of Ca2+ uptake by the Ca2+ load of intracellular stores. The concentration-inhibition relationship between the Ca2+ load and the rate of Ca2+ uptake was highly supralinear (slope factor >/= 4). IC50 and maximum of the dose-inhibition curve, but not the slope factor were a function of the extravesicular free Ca2+ concentration. A series of three logistic equations derived from our data allowed an appropriate description of the behavior of Ca2+ uptake. Our results suggest, in addition to its well known activation by cytosolic Ca2+ concentration, a highly supralinear feedback inhibition of Ca2+ uptake by the Ca2+ load of intracellular stores. The steepness of the feedback inhibition might have a profound effect on spatial and temporal behavior of the Ca2+ signal.
authors.affiliation: Division of Infectious Diseases, University Hospital, Geneva, Switzerland.
authors.forename: C J
authors.initials: CJ
authors.lastname: Favre
authors.forename: J
authors.initials: J
authors.lastname: Schrenzel
authors.forename: J
authors.initials: J
authors.lastname: Jacquet
authors.forename: D P
authors.initials: DP
authors.lastname: Lew
authors.forename: K H
authors.initials: KH
authors.lastname: Krause
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002474:Cell-Free System; D002614:Chelating Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005246:Feedback; D006096:Gramicidin / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007700:Kinetics; D008433:Mathematics; D008962:Models, Theoretical; D008985:Monensin / Q000494:pharmacology; D009550:Nigericin / Q000494:pharmacology; D010070:Oxalates / Q000494:pharmacology; D014634:Valinomycin / Q000494:pharmacology
chemical_list: D002132:Calcium Radioisotopes; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D010070:Oxalates; D006096:Gramicidin; D014634:Valinomycin; D008985:Monensin; D000252:Calcium-Transporting ATPases; D009550:Nigericin; D002118:Calcium