scholarly journals The action of selective CRAC channel blockers is affected by the Orai pore geometry

Cell Calcium ◽  
2013 ◽  
Vol 53 (2) ◽  
pp. 139-151 ◽  
Author(s):  
Isabella Derler ◽  
Rainer Schindl ◽  
Reinhard Fritsch ◽  
Peter Heftberger ◽  
Maria Christine Riedl ◽  
...  
Keyword(s):  
Pore Geometry ◽  
Channel Blockers ◽  
Crac Channel

Store-Operated Ca2+ Channels: Mechanism, Function, Pharmacology, and Therapeutic Targets

2021 ◽  
Vol 61 (1) ◽  
pp. 629-654
Author(s):  
Daniel Bakowski ◽  
Fraser Murray ◽  
Anant B. Parekh
Keyword(s):  
Channel Blockers ◽  
Channel Activity ◽  
Loss Of Function ◽  
Crac Channels ◽  
Crac Channel ◽  
Major Route ◽  
And Function ◽  
Therapeutic Perspective ◽  
Poor Efficacy ◽  
Ca2 Channels

Calcium (Ca2+) release–activated Ca2+ (CRAC) channels are a major route for Ca2+ entry in eukaryotic cells. These channels are store operated, opening when the endoplasmic reticulum (ER) is depleted of Ca2+, and are composed of the ER Ca2+ sensor protein STIM and the pore-forming plasma membrane subunit Orai. Recent years have heralded major strides in our understanding of the structure, gating, and function of the channels. Loss-of-function and gain-of-function mutants combined with RNAi knockdown strategies have revealed important roles for the channel in numerous human diseases, making the channel a clinically relevant target. Drugs targeting the channels generally lack specificity or exhibit poor efficacy in animal models. However, the landscape is changing, and CRAC channel blockers are now entering clinical trials. Here, we describe the key molecular and biological features of CRAC channels, consider various diseases associated with aberrant channel activity, and discuss targeting of the channels from a therapeutic perspective.

Ca2+ release-activated Ca2+ channels are responsible for histamine-induced Ca2+ entry, permeability increase, and interleukin synthesis in lymphatic endothelial cells

2020 ◽  
Vol 318 (5) ◽  
pp. H1283-H1295 ◽  
Author(s):  
Hongjiang Si ◽  
Jian Wang ◽  
Cynthia J. Meininger ◽  
Xu Peng ◽  
David C. Zawieja ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Immune Surveillance ◽  
Endothelial Barrier ◽  
Channel Blockers ◽  
Lymphatic Endothelial Cells ◽  
Histamine Stimulation ◽  
Cellular Effects ◽  
Crac Channels ◽  
Crac Channel

The lymphatic functions in maintaining lymph transport, and immune surveillance can be impaired by infections and inflammation, thereby causing debilitating disorders, such as lymphedema and inflammatory bowel disease. Histamine is a key inflammatory mediator known to trigger vasodilation and vessel hyperpermeability upon binding to its receptors and evoking intracellular Ca2+ ([Ca2+]i) dynamics for downstream signal transductions. However, the exact molecular mechanisms beneath the [Ca2+]i dynamics and the downstream cellular effects have not been elucidated in the lymphatic system. Here, we show that Ca2+ release-activated Ca2+ (CRAC) channels, formed by Orai1 and stromal interaction molecule 1 (STIM1) proteins, are required for the histamine-elicited Ca2+ signaling in human dermal lymphatic endothelial cells (HDLECs). Blockers or antagonists against CRAC channels, phospholipase C, and H1R receptors can all significantly diminish the histamine-evoked [Ca2+]i dynamics in lymphatic endothelial cells (LECs), while short interfering RNA-mediated knockdown of endogenous Orai1 or STIM1 also abolished the Ca2+ entry upon histamine stimulation in LECs. Furthermore, we find that histamine compromises the lymphatic endothelial barrier function by increasing the intercellular permeability and disrupting vascular endothelial-cadherin integrity, which is remarkably attenuated by CRAC channel blockers. Additionally, the upregulated expression of inflammatory cytokines, IL-6 and IL-8, after histamine stimulation was abolished by silencing Orai1 or STIM1 with RNAi in LECs. Taken together, our data demonstrated the essential role of CRAC channels in mediating the [Ca2+]i signaling and downstream endothelial barrier and inflammatory functions induced by histamine in the LECs, suggesting a promising potential to relieve histamine-triggered vascular leakage and inflammatory disorders in the lymphatics by targeting CRAC channel functions.

Polymorphic phase transition of a membrane protein - analysis of continuous diffuse electron diffraction intensity

1986 ◽  
Vol 44 ◽  
pp. 166-167
Author(s):  
Douglas L. Dorset ◽  
Andrew K. Massalski
Keyword(s):  
Molecular Sieve ◽  
Three Dimensional ◽  
Pore Geometry ◽  
Two Dimensional ◽  
Diffraction Intensity ◽  
Polymorphic Phase Transition ◽  
E Coli ◽  
Crystallographic Study ◽  
Hexagonal Form ◽  
Polymorphic Forms

Matrix porin, the ompF gene product of E. coli, has been the object of a electron crystallographic study of its pore geometry in an attempt to understand its function as a membrane molecular sieve. Three polymorphic forms have been found for two-dimensional crystals reconstituted in phospholipid, two hexagonal forms with different lipid content and an orthorhombic form coexisting with and similar to the hexagonal form found after lipid loss. In projection these have been shown to retain the same three-fold pore triplet geometry and analyses of three-dimensional data reveal that the small hexagonal and orthorhombic polymorphs have similar structure as well as unit cell spacings.

Secondary medical prevention in patients with peripheral arterial disease - Prescriptions of vascular surgeons and medical doctors (angiologists) in a multidisciplinary vascular centre

VASA ◽  
2010 ◽  
Vol 39 (2) ◽  
pp. 145-152 ◽  
Author(s):  
Klein-Weigel ◽  
Gutsche-Petrak ◽  
Wolbergs ◽  
Köning ◽  
Flessenkamper
Keyword(s):  
Peripheral Arterial Disease ◽  
Oral Anticoagulants ◽  
Arterial Disease ◽  
Disease Stage ◽  
Channel Blockers ◽  
Medical Doctors ◽  
Vascular Surgeon ◽  
Medical Prevention ◽  
Number Of Patients ◽  
Peripheral Arterial

Background: We compared medical secondary prevention in patients with peripheral arterial disease stage II (Fontaine) located in the femoro-popliteal artery managed by vascular surgeons and medical doctors / angiologists in our multidisciplinary vascular center. Patients and methods: We retrospectively analyzed demission protocols of in-hospital treatments between 01.01.2007 and 20.06.2008. Results: We surveyed 264 patients (54.2 % women; mean age 67.52 ± 8.98 yrs), 179 (67.8 %) primarily treated by medical doctors / angiologists and 85 (32.2 %) primarily managed by vascular surgeons. Medical doctors / angiologists treated more women (n = 109) than men (n = 34), (p = 0.002) and documented smoking and diabetes mellitus more often (p < 0.001) than vascular surgeons. Besides, patients had similar cardiovascular risk profiles and concomitant diseases, vascular surgeons prescribed 5.47 ± 2.26 drugs, medical doctors / angiologists 6.37 ± 2.67 (p = 0.005). Overall, 239 (90.5 %) patients were on aspirin, 180 (68.2 %) on clopidogrel, and 18 (6.9 %) on oral anticoagulants. Significantly more patients treated by medical doctors / angiologists received clopidogrel (169 versus 11; p < 0.001), significantly more surgical patients received oral anticoagulants (11 versus 7; p = 0.016). The number of patients without prescriptions for any antithrombotic therapy was 6 (6.9 %) in patients treated by vascular surgeons and 0 (0 %) in patients managed by medical doctors / angiologists (p = 0.001). Prescription-rates of β-blockers, ACE-inhibitors, Angiotensin II-antangonists, calcium channel blockers, and diuretics were statistically not different between the two disciplines, but statins were prescribed significantly more often by medical doctors / angiologists (139 versus 49; p < 0001). With the exceptions of Clopidogrel (women > men) and diuretics (men > women) we observed no gender-specific prescriptions. Conclusions: We observed high prescriptions rates of secondary medical prevention in patients primarily treated by medical doctors / angiologists and vascular surgeons. We believe that this result is highly influenced by our multidisciplinary approach. Nevertheless, efforts have to be made to raise vascular surgeon’s awareness of statin use and complete prescription of antithrombotic and antiplatelet drugs.

An Anthrone-Based Kv7.2/7.3 Channel Blocker with Improved Properties for the Investigation of Psychiatric and Neurodegenerative Disorders

2019 ◽  
Author(s):  
Jacob Porter ◽  
Oscar Vivas-Rodriguez ◽  
C. David Weaver ◽  
Eamonn Dickson ◽  
Abdulmohsen Alsafran ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Neurodegenerative Disorders ◽  
Channel Blocker ◽  
Optimal Combination ◽  
Channel Blockers ◽  
Enolate Alkylation ◽  
Cyp Inhibition ◽  
Alkylation Reactions ◽  
Metabolic Instability

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (JDP-107) with an optimal combination of potency (IC<sub>50</sub>= 0.16 𝜇M in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.

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