ORAI channels in cellular remodeling of cardiorespiratory disease

Abstract

Cardiorespiratory disease, which includes systemic arterial hypertension, restenosis, atherosclerosis, pulmonary arterial hypertension, asthma, and chronic obstructive pulmonary disease (COPD) are highly prevalent and devastating diseases with limited therapeutic modalities. A common pathophysiological theme to these diseases is cellular remodeling, which is contributed by changes in expression and activation of ion channels critical for either excitability or growth. Calcium (Ca²⁺) signaling and specifically ORAI Ca²⁺ channels have emerged as significant regulators of smooth muscle, endothelial, epithelial, platelet, and immune cell remodeling. This review details the dysregulation of ORAI in cardiorespiratory diseases, and how this dysregulation of ORAI contributes to cellular remodeling.

Keywords: ARC; Asthma; Atherosclerosis; COPD; CRAC; Hypertension; ORAI; Pulmonary hypertension; Remodeling; Restenosis; SOCE; STIM.

Figure 1.. SOCE mediated by ORAI channels.

Binding of agonists to PLC-coupled receptors generates the secondary messenger IP₃. IP₃ induces ER Ca²⁺ release through the IP₃ receptor. Following ER Ca²⁺ release, Ca²⁺ dissociates from the EF hand of STIM and triggers STIM to oligomerize, migrate towards the ER-PM junction, trap, and activate ORAI channels. This activation causes a large Ca²⁺ influx from the extracellular milieu into the cytosol, which refills ER Ca²⁺ stores through SERCA and create cytosolic Ca²⁺ microdomains that are sensed by downstream cell signaling effectors and transcription factors, activating gene programs to support metabolism, proliferation and migration.

Figure 2.. Mechanism of SOCE activation.

Under resting conditions, STIM proteins exist as inactive dimers in the ER membrane. STIM low-affinity luminal EF hand domains are bound to Ca²⁺, and the inhibitory coiled coil-1 (CC1) domain occludes the STIM-ORAI activating region (SOAR). Upon ER Ca²⁺ store depletion, Ca²⁺ dissociates from EF hand domains, which causes STIM to undergo a conformational change and gain an extended conformation, which exposes its cytosolic SOAR domain. SOAR dimers are then able to physically trap and gate PM-located ORAI Ca²⁺ channels leading to activation of SOCE.

Figure 3.. Role of ORAI channels in cellular remodeling in cardiorespiratory disease.

Summary of functions of ORAI channels in A) SAH and PAH, B) restenosis, C) atherosclerosis, D) asthma and COPD are listed under each cell type. Marked in bold have been studied exclusively in that disease, while those marked in italic have been speculated based on other tissues or diseases. A question mark indicates that the role of ORAI in this cell type is unknown.