Ca²⁺ pool emptying stimulates Ca²⁺ entry activated by S- nitrosylation

The entry of Ca²⁺ following Ca²⁺ pool release is a major component of Ca²⁺ signals; yet despite intense study, how 'store-operated' entry channels are activated is unresolved. Because S-nitrosylation has become recognized as an important regulatory modification of several key channel proteins, its role in Ca²⁺ entry was investigated. A novel class of lipophilic NO donors activated Ca²⁺ entry independent of the well defined NO target, guanylate cyclase. Strikingly similar entry of Ca²⁺ induced by cell permeant alkylators indicated that this Ca²⁺ entry process was activated through thiol modification. Significantly, Ca²⁺ entry activated by either NO donors or alkylators was highly stimulated by Ca²⁺ pool depletion, which increased both the rate of Ca²⁺ release and the sensitivity to thiol modifiers. The results indicate that S-nitrosylation underlies activation of an important store-operated Ca²⁺ entry mechanism.