Glucocorticoids prolong Ca(2+) transients in hippocampal-derived H19-7 neurons by repressing the plasma membrane Ca(2+)-ATPase-1.
Calcium ions (Ca(2+)) play an important role in mediating an array of structural and functional responses in cells. In hippocampal neurons, elevated glucocorticoid (GC) levels, as seen during stress, perturb calcium homeostasis and result in altered neuronal excitability and viability. Ligand- and voltage-gated calcium channels have been the presumed targets of hormonal regulation; however, circumstantial evidence has suggested the possibility that calcium extrusion might be an important target of GC regulation. Here we demonstrate that GC-induced repression of the plasma membrane Ca(2+)-ATPase-1 (PMCA1) is an essential determinant of intracellular Ca(2+) levels ([Ca(2+)](i)) in cultured hippocampal H19-7 cells. In particular, GC treatment caused a prolongation of agonist-evoked elevation of [Ca(2+)](i) that was prevented by the expression of exogenous PMCA1. Furthermore, selective inhibition of PMCA1 using the RNA interference technique caused prolongation of Ca(2+) transients in the absence of GC treatment. Taken together, these observations suggest that GC-mediated repression of PMCA1 is both necessary and sufficient to increase agonist-evoked Ca(2+) transients by down-regulating Ca(2+) extrusion mechanisms in the absence of effects on calcium channels. Prolonged exposure to GCs, resulting in concomitant accumulation of [Ca(2+)](i), is likely to compromise neuronal function and viability.
Bhargava
Aditi
A
Department of Medicine, Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143, USA.
Mathias
Robert S
RS
McCormick
James A
JA
Dallman
Mary F
MF
Pearce
David
D
D020013:Calcium Signaling / Q000187:drug effects*; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins; D002478:Cells, Cultured; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008967:Molecular Biology / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D053499:Plasma Membrane Calcium-Transporting ATPases; D034622:RNA Interference; D017470:Receptors, Glutamate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
C506952:ATP2B1 protein, human; D027682:Cation Transport Proteins; D005938:Glucocorticoids; D017470:Receptors, Glutamate; D053499:Plasma Membrane Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases