Store-operated calcium channels: Potential target for the therapy of hypertension

Abstract

Effective therapy of hypertension represents a key strategy for reducing the burden of cardiovascular disease and its associated mortality. The significance of voltage dependent L-type Ca 2+ channels to Ca 2+ influx, and of their regulatory mechanisms in the development of heart disease, is well established. A wide variety of L-type Ca 2+ channel inhibitors and Ca 2+ antagonists have been found to be beneficial not only in the treatment of hypertension, but also in myocardial infarction and heart failure. Over the past two decades, another class of Ca 2+ channel-the voltage independent store-operated Ca 2+ channel-has been implicated in the regulation and fine tuning of Ca 2+ entry in both cardiac and smooth muscle cells. Storeoperated Ca 2+ channels are activated by the depletion of Ca 2+ stores within the endoplasmic/sarcoplasmic reticulum, or by low levels of cytosolic Ca 2+ , thereby facilitating agonist-induced Ca 2+ influx. Store-operated Ca 2+ entry through this pivotal pathway involves both stromal interaction molecule (STIM) and Orai channels. Different degrees of changes in these proteins are considered to promote Ca 2+ entry and hence contribute to the pathogenesis of cardiovascular dysfunction. Several blockers of storeoperated Ca 2+ channels acting at the level of both STIM and Orai channels have been shown to depress Ca 2+ influx and lower blood pressure. However, their specificity, safety, and clinical significance remain to be established. Thus, there is an ongoing challenge in the development of selective inhibitors of store-operated Ca 2+ channels that act in vascular smooth muscles for the improved treatment of hypertension.

ARMC Subfamily: Structures, Functions, Evolutions, Interactions, and Diseases

“…On the one hand, CRACR2A acts as a cytoplasmic calcium sensor that facilitates the clustering of ORAI1 and STIM1 at the junctional regions between the plasma membrane and the endoplasmic reticulum at low Ca2+ concentrations (Srikanth et al, 2010). On the other hand, hypertension is positively correlated with SOCE (Bhullar et al, 2019). This finding suggests that ARMC3 interacts and interferes with CRACR2A and thus inhibits the expression of ORAI1 and STIM1 to suppress hypertension.…”

Sarsasapogenin blocks ox-LDL-stimulated vascular smooth muscle cell proliferation, migration, and invasion through suppressing STIM1 expression

“…Store-operated calcium channel (SOCC) has been revealed to be expressed in immune cells, VSMCs, and endothelial cells and participate in immunologic functions, vascular contraction, cell proliferation, and migration ( 16 , 17 ). A large number of studies have specified the pivotal role of SOCC in cardiovascular diseases ( 18 ), such as hypertension ( 19 ) and AS ( 20 ). Stromal interaction molecule 1 (STIM1) located in the endoplasmic reticulum membrane and Orai are pivotal components of canonical store-operated calcium entry (SOCE) ( 21 ).…”

Ion Channels and Transporters as Therapeutic Agents: From Biomolecules to Supramolecular Medicinal Chemistry

“…In therapy, channel blockers are used to treat numerous diseases. As a well-known example, selective Ca 2+ -channel blockers are anti-hypertensive drugs [32]. Several types of ion transporters are being considered as therapeutic targets for ischemic stroke [33].…”

“…Overall, selectivity is indeed key, and there is a recent trend to employ biologics to achieve it, including engineered antibodies, nanobodies, and venom-derived peptides In therapy, channel blockers are used to treat numerous diseases. As a well-known example, selective Ca 2+ -channel blockers are anti-hypertensive drugs [32]. Several types of ion transporters are being considered as therapeutic targets for ischemic stroke [33].…”