Cardiovascular system STIM1/Orai1-mediated store-operated Ca2+ entry in cardiovascular disease

Abstract

The concept of store operated Ca2+ entry (SOCE), or capacitative Ca2+ entry (CCE) as it was originally termed by Jim Putney, stemmed from a series of insightful experiments he conducted in the late 1970s and formalized in a 1986 hypothesis paper. SOCE refers to a mode of regulated Ca2+ entry whereby the discharge of intracellular Ca2+ stores couples and activates a Ca2+ entry route across the plasma membrane. The last 5 years brought about a great understanding of the mode of activation and regulation of SOCE through the discovery of STIM1 and Orai1 as essential components of this Ca2+ entry pathway. STIM1 senses Ca2+ stores discharge in the endoplasmic reticulum through a luminal low affinity EF-hand domain and directly communicates this information, via protein-protein interaction, to the plasma membrane SOC channel constituted by Orai1,causing its activation. More recently, evidence suggests that STIM1 and Orai1 proteins contribute to a number of cardiovascular diseases such as cardiac hypertrophy, thrombosis, hypertension, atherosclerosis, restenosis and vascular smooth muscle proliferation and migration, an important determinant in the development and progression of several vascular occlusive diseases such as hypertension, restenosis and atherosclerosis. In this review, we will present a retrospective analysis of the current literature suggesting involvement of STIM1 and Orai1 in cardiovascular diseases and the potential therapeutic exploitation of these molecules for treatment of these diseases.