Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology

Abstract

Ca2+ ion channels are critical in a variety of physiological events, including cell growth, differentiation, gene transcription and apoptosis. One such essential entry pathway for calcium into the cell is the Ca2+ release-activated Ca2+ (CRAC) channel. It consists of the Ca2+ sensing protein, stromal interaction molecule 1 (STIM1) located in the endoplasmic reticulum (ER) and a Ca2+ ion channel Orai in the plasma membrane. The Orai channel family includes three homologues Orai1, Orai2 and Orai3. While Orai1 is the “classical” Ca2+ ion channel within the CRAC channel complex and plays a universal role in the human body, there is increasing evidence that Orai2 and Orai3 are important in specific physiological and pathophysiological processes. This makes them an attractive target in drug discovery, but requires a detailed understanding of the three Orai channels and, in particular, their differences. Orai channel activation is initiated via Ca2+ store depletion, which is sensed by STIM1 proteins, and induces their conformational change and oligomerization. Upon STIM1 coupling, Orai channels activate to allow Ca2+ permeation into the cell. While this activation mechanism is comparable among the isoforms, they differ by a number of functional and structural properties due to non-conserved regions in their sequences. In this review, we summarize the knowledge as well as open questions in our current understanding of the three isoforms in terms of their structure/function relationship, downstream signaling and physiology as well as pathophysiology.

Highlighting the Multifaceted Role of Orai1 N-Terminal- and Loop Regions for Proper CRAC Channel Functions

“…The family of human Orai proteins comprises three homologs (hOrai1-3) that, in collective with the sensor proteins STIM1 and STIM2, choreograph Ca 2+ signaling in a graded and diverse fashion [36]. Even though three murine orthologs have also been identified [37,38], herein, the simplified designations Orai1, Orai2 and Orai3 are deployed to refer to the human proteins hOrai1-hOrai3 only [22,[39][40][41][42]. However, the Orai proteins share general structural features and are associated with a comparatively high degree of sequence conservation within their transmembrane domains, but they are considerable different from other Ca 2+ -selective channels [22,[39][40][41][42].…”

Deciphering Molecular Mechanisms and Intervening in Physiological and Pathophysiological Processes of Ca2+ Signaling Mechanisms Using Optogenetic Tools

“…Interestingly, LOV2 integration only allowed to transfer light-mediated Orai1 activation in the presence of a constitutively active point mutation (P245T). The additional single amino acid substitution (H171Y) provides indications for the necessity of a correct interplay of cytosolic segments, as we recently demonstrated for the interplay of salt-bridge interactions within the cytosolic triangles [ 59 , 61 ].…”

“…They are encoded by pentameric channel complexes consisting of distinct Orai isoforms, specifically three Orai1 and two Orai3 subunits [ 60 ]. These heteropentameric Orai1/Orai3 ion channels are particularly relevant in disease states, including cardiohypertrophy, injured smooth muscle cells, and breast, lung, and prostate cancer [ 61 , 62 ].…”

Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

“…In mammals, there are three Orai homologs (Orai1, 2 and 3) wherein Orai1 is the most studied among the three and plays a critical role in cellular physiology [ 16 , 18 ], while the functional significance of Orai2 and Orai3 is still emerging in nature [ 19 , 20 , 21 ]. The role of Orai1 in driving breast, lung, brain and prostate tumorigenesis is well documented [ 6 , 22 ].…”