Abstract
In many nonexcitable cells, hormones and neurotransmitters activate Na(+) influx and mobilize Ca(2+) from intracellular stores. The stores are replenished by Ca(2+) influx via "store-operated" Ca(2+) channels (SOC). The main routes of Na(+) entry in these cells are unresolved, and no role for Na(+) in signaling has been recognized. We demonstrate that the SOC are a major Na(+) entry route in arterial myocytes. Unloading of the Ca(2+) stores with cyclopiazonic acid (a sarcoplasmic reticulum Ca(2+) pump inhibitor) and caffeine induces a large external Na(+)-dependent rise in the cytosolic Na(+) concentration. One component of this rise in cytosolic Na(+) concentration is likely due to Na(+)/Ca(2+) exchange; it depends on elevation of cytosolic Ca(2+) and is insensitive to 10 mM Mg(2+) and 10 microM La(3+). Another component is inhibited by Mg(2+) and La(3+), blockers of SOC; this component persists in cells preloaded with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid to buffer Ca(2+) transients and prevent Na(+)/Ca(2+) exchange-mediated Na(+) entry. This Na(+) entry apparently is mediated by SOC. The Na(+) entry influences Na(+) pump activity and Na(+)/Ca(2+) exchange and has unexpectedly large effects on cell-wide Ca(2+) signaling. The SOC pathway may be a general mechanism by which Na(+) participates in signaling in many types of cells.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiotensin II / pharmacology
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Animals
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Caffeine / pharmacology
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Calcium / pharmacokinetics
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Calcium Channels, L-Type / physiology
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Calcium Signaling / physiology*
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Cardiotonic Agents / pharmacology
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Cells, Cultured
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Chelating Agents / pharmacology
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Cytosol / enzymology
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Dinucleoside Phosphates / pharmacology
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Egtazic Acid / analogs & derivatives
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Egtazic Acid / pharmacology
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Extracellular Space / metabolism
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Female
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Fluorescent Dyes
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Fura-2
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Indoles / pharmacology
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Magnesium / pharmacology
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Mesenteric Arteries / cytology
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Mesenteric Arteries / enzymology
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / enzymology*
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Ouabain / pharmacology
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Phenylephrine / pharmacology
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Phosphodiesterase Inhibitors / pharmacology
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Rats
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Rats, Sprague-Dawley
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Sarcoplasmic Reticulum / enzymology
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Sodium / pharmacokinetics*
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Sodium-Calcium Exchanger / metabolism*
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Sodium-Potassium-Exchanging ATPase / metabolism*
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Vasoconstrictor Agents / pharmacology
Substances
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Calcium Channels, L-Type
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Cardiotonic Agents
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Chelating Agents
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Dinucleoside Phosphates
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Enzyme Inhibitors
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Fluorescent Dyes
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Indoles
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Phosphodiesterase Inhibitors
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Sodium-Calcium Exchanger
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Vasoconstrictor Agents
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Angiotensin II
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1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
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Phenylephrine
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cytidylyl adenosine
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Caffeine
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Egtazic Acid
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Ouabain
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Sodium
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Sodium-Potassium-Exchanging ATPase
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Magnesium
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Calcium
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Fura-2
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cyclopiazonic acid