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

2021 ◽  
Vol 22 (15) ◽  
pp. 8020
Author(s):  
Adéla Tiffner ◽  
Isabella Derler
Keyword(s):  
Ion Channel ◽  
Activation Mechanism ◽  
Downstream Signaling ◽  
Entry Pathway ◽  
Store Depletion ◽  
Open Questions ◽  
Crac Channel ◽  
Function Relationship ◽  
Differentiation Gene ◽  
Orai Channels

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.

scholarly journals Sequential Activation and Inactivation of Dishevelled in the Wnt/β-Catenin Pathway by Casein Kinases

2011 ◽  
Vol 286 (12) ◽  
pp. 10396-10410 ◽  
Author(s):  
Ondrej Bernatik ◽  
Ranjani Sri Ganji ◽  
Jacomijn P. Dijksterhuis ◽  
Peter Konik ◽  
Igor Cervenka ◽  
...  
Keyword(s):  
Activation Mechanism ◽  
Loss Of Function ◽  
Casein Kinase 1 ◽  
Downstream Signaling ◽  
C Terminus ◽  
Pathway Activation ◽  
Function Loss ◽  
Domain Mapping ◽  
Casein Kinases ◽  
Sequential Activation

Dishevelled (Dvl) is a key component in the Wnt/β-catenin signaling pathway. Dvl can multimerize to form dynamic protein aggregates, which are required for the activation of downstream signaling. Upon pathway activation by Wnts, Dvl becomes phosphorylated to yield phosphorylated and shifted (PS) Dvl. Both activation of Dvl in Wnt/β-catenin signaling and Wnt-induced PS-Dvl formation are dependent on casein kinase 1 (CK1) δ/ϵ activity. However, the overexpression of CK1 was shown to dissolve Dvl aggregates, and endogenous PS-Dvl forms irrespective of whether or not the activating Wnt triggers the Wnt/β-catenin pathway. Using a combination of gain-of-function, loss-of-function, and domain mapping approaches, we attempted to solve this discrepancy regarding the role of CK1ϵ in Dvl biology. We analyzed mutual interaction of CK1δ/ϵ and two other Dvl kinases, CK2 and PAR1, in the Wnt/β-catenin pathway. We show that CK2 acts as a constitutive kinase whose activity is required for the further action of CK1ϵ. Furthermore, we demonstrate that the two consequences of CK1ϵ phosphorylation are separated both spatially and functionally; first, CK1ϵ-mediated induction of TCF/LEF-driven transcription (associated with dynamic recruitment of Axin1) is mediated via a PDZ-proline-rich region of Dvl. Second, CK1ϵ-mediated formation of PS-Dvl is mediated by the Dvl3 C terminus. Furthermore, we demonstrate with several methods that PS-Dvl has decreased ability to polymerize with other Dvls and could, thus, act as the inactive signaling intermediate. We propose a multistep and multikinase model for Dvl activation in the Wnt/β-catenin pathway that uncovers a built-in de-activation mechanism that is triggered by activating phosphorylation of Dvl by CK1δ/ϵ.

scholarly journals Calmidazolium and arachidonate activate a calcium entry pathway that is distinct from store-operated calcium influx in HeLa cells

2004 ◽  
Vol 381 (3) ◽  
pp. 929-939 ◽  
Author(s):  
Claire M. PEPPIATT ◽  
Anthony M. HOLMES ◽  
Jeong T. SEO ◽  
Martin D. BOOTMAN ◽  
Tony J. COLLINS ◽  
...  
Keyword(s):  
Hela Cells ◽  
Calcium Influx ◽  
Differential Sensitivity ◽  
Excitable Cells ◽  
Hormonal Stimulation ◽  
Calmodulin Antagonist ◽  
Alternative Pathways ◽  
Entry Pathway ◽  
Store Depletion ◽  
Stimulation Of

Agonists that deplete intracellular Ca2+ stores also activate Ca2+ entry, although the mechanism by which store release and Ca2+ influx are linked is unclear. A potential mechanism involves ‘store-operated channels’ that respond to depletion of the intracellular Ca2+ pool. Although SOCE (store-operated Ca2+ entry) has been considered to be the principal route for Ca2+ entry during hormonal stimulation of non-electrically excitable cells, recent evidence has suggested that alternative pathways activated by metabolites such as arachidonic acid are responsible for physiological Ca2+ influx. It is not clear whether such messenger-activated pathways exist in all cells, whether they are truly distinct from SOCE and which metabolites are involved. In the present study, we demonstrate that HeLa cells express two pharmacologically and mechanistically distinct Ca2+ entry pathways. One is the ubiquitous SOCE route and the other is an arachidonate-sensitive non-SOCE. We show that both these Ca2+ entry pathways can provide long-lasting Ca2+ elevations, but that the channels are not the same, based on their differential sensitivity to 2-aminoethoxydiphenyl borate, LOE-908 {(R,S)-(3,4-dihydro-6,7-dimethoxy-isochinolin-1-yl)-2-phenyl-N,N-di[2-(2,3,4-trimethoxyphenyl)ethyl]acetamid mesylate} and gadolinium. In addition, non-SOCE and not SOCE was permeable to strontium. Furthermore, unlike SOCE, the non-SOCE pathway did not require store depletion and was not sensitive to displacement of the endoplasmic reticulum from the plasma membrane using jasplakinolide or ionomycin pretreatment. These pathways did not conduct Ca2+ simultaneously due to the dominant effect of arachidonate, which rapidly curtails SOCE and promotes Ca2+ influx via non-SOCE. Although non-SOCE could be activated by exogenous application of arachidonate, the most robust method for stimulation of this pathway was application of the widely used calmodulin antagonist calmidazolium, due to its ability to activate phospholipase A2.

scholarly journals Evidence for a receptor-activated Ca2+ entry pathway independent from Ca2+ store depletion in endothelial cells

Cell Calcium ◽  
2008 ◽  
Vol 43 (1) ◽  
pp. 83-94 ◽  
Author(s):  
H. Jousset ◽  
R. Malli ◽  
N. Girardin ◽  
W.F. Graier ◽  
N. Demaurex ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Entry Pathway ◽  
Store Depletion

scholarly journals Activation mechanism of the M2 ion channel of influenza A virus

2000 ◽  
Vol 40 (supplement) ◽  
pp. S32
Author(s):  
A. Okada ◽  
T. Miura ◽  
H. Takeuchi
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Activation Mechanism

scholarly journals Membrane voltage-dependent activation mechanism of the bacterial flagellar protein export apparatus

2021 ◽  
Vol 118 (22) ◽  
pp. e2026587118
Author(s):  
Tohru Minamino ◽  
Yusuke V. Morimoto ◽  
Miki Kinoshita ◽  
Keiichi Namba
Keyword(s):  
Ion Channel ◽  
Protein Transport ◽  
Atp Hydrolysis ◽  
Protein Export ◽  
Membrane Voltage ◽  
Activation Mechanism ◽  
Dependent Manner ◽  
Concentration Difference ◽  
Flagellar Protein ◽  
External Ph

The proton motive force (PMF) consists of the electric potential difference (Δψ), which is measured as membrane voltage, and the proton concentration difference (ΔpH) across the cytoplasmic membrane. The flagellar protein export machinery is composed of a PMF-driven transmembrane export gate complex and a cytoplasmic ATPase ring complex consisting of FliH, FliI, and FliJ. ATP hydrolysis by the FliI ATPase activates the export gate complex to become an active protein transporter utilizing Δψ to drive proton-coupled protein export. An interaction between FliJ and a transmembrane ion channel protein, FlhA, is a critical step for Δψ-driven protein export. To clarify how Δψ is utilized for flagellar protein export, we analyzed the export properties of the export gate complex in the absence of FliH and FliI. The protein transport activity of the export gate complex was very low at external pH 7.0 but increased significantly with an increase in Δψ by an upward shift of external pH from 7.0 to 8.5. This observation suggests that the export gate complex is equipped with a voltage-gated mechanism. An increase in the cytoplasmic level of FliJ and a gain-of-function mutation in FlhA significantly reduced the Δψ dependency of flagellar protein export by the export gate complex. However, deletion of FliJ decreased Δψ-dependent protein export significantly. We propose that Δψ is required for efficient interaction between FliJ and FlhA to open the FlhA ion channel to conduct protons to drive flagellar protein export in a Δψ-dependent manner.

Revealing dynamically-organized receptor ion channel clusters in live cells by a correlated electric recording and super-resolution single-molecule imaging approach

2018 ◽  
Vol 20 (12) ◽  
pp. 8088-8098 ◽  
Author(s):  
Rajeev Yadav ◽  
H. Peter Lu
Keyword(s):  
Ion Channel ◽  
Single Molecule ◽  
Super Resolution ◽  
Live Cells ◽  
Imaging Approach ◽  
Resolution Imaging ◽  
Function Relationship ◽  
Bleaching Step ◽  
Relationship Of ◽  
Resolution Single

Correlating single-molecule fluorescence photo-bleaching step analysis and single-molecule super-resolution imaging, our findings for the clustering effect of the NMDA receptor ion channel on the live cell membranes provide a new and significant understanding of the structure–function relationship of NMDA receptors.

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