Na(+) entry via store-operated channels modulates Ca(2+) signaling in arterial myocytes.
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.
Arnon
A
A
Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Hamlyn
J M
JM
Blaustein
M P
MP
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000493:pharmacokinetics; D020746:Calcium Channels, L-Type / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D015226:Dinucleoside Phosphates / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2; D007211:Indoles / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000166:cytology / Q000201:enzymology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D010042:Ouabain / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D012964:Sodium / Q000493:pharmacokinetics*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D002614:Chelating Agents; D015226:Dinucleoside Phosphates; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D019831:Sodium-Calcium Exchanger; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D010656:Phenylephrine; C013907:cytidylyl adenosine; D002110:Caffeine; D004533:Egtazic Acid; D010042:Ouabain; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium; D002118:Calcium; D016257:Fura-2; C000543:cyclopiazonic acid