Na(+) entry via store-operated channels modulates Ca(2+) signaling in arterial myocytes

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.