Na+entry via store-operated channels modulates Ca2+signaling in arterial myocytes

Abstract

In many nonexcitable cells, hormones and neurotransmitters activate Na⁺ influx and mobilize Ca²⁺ from intracellular stores. The stores are replenished by Ca²⁺influx via “store-operated” Ca²⁺ 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 Ca²⁺stores with cyclopiazonic acid (a sarcoplasmic reticulum Ca²⁺ 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⁺/Ca²⁺exchange; it depends on elevation of cytosolic Ca²⁺ and is insensitive to 10 mM Mg²⁺ and 10 μM La³⁺. Another component is inhibited by Mg²⁺ and La³⁺, blockers of SOC; this component persists in cells preloaded with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid to buffer Ca²⁺ transients and prevent Na⁺/Ca²⁺exchange-mediated Na⁺ entry. This Na⁺ entry apparently is mediated by SOC. The Na⁺ entry influences Na⁺ pump activity and Na⁺/Ca²⁺exchange and has unexpectedly large effects on cell-wide Ca²⁺ signaling. The SOC pathway may be a general mechanism by which Na⁺ participates in signaling in many types of cells.