STIM1/Orai1-mediated store-operated Ca²⁺ entry: The tip of the iceberg

Highly efficient mechanisms regulate intracellular calcium (Ca²⁺) levels. The recent discovery of new components linking intracellular Ca²⁺ stores to plasma membrane Ca²⁺ entry channels has brought new insight into the understanding of Ca²⁺ homeostasis. Stromal interaction molecule 1 (STIM1) was identified as a Ca²⁺ sensor essential for Ca²⁺ store depletion-triggered Ca²⁺ influx. Orai1 was recognized as being an essential component for the Ca²⁺ release-activated Ca²⁺ (CRAC) channel. Together, these proteins participate in store-operated Ca²⁺ channel function. Defective regulation of intracellular Ca²⁺ is a hallmark of several diseases. In this review, we focus on Ca²⁺ regulation by the STIM1/Orai1 pathway and review evidence that implicates STIM1/ Orai1 in several pathological conditions including cardiovascular and pulmonary diseases, among others.