Physiological Functions of CRAC Channels

2021 ◽  
Vol 84 (1) ◽  
Author(s):  
Scott M. Emrich ◽  
Ryan E. Yoast ◽  
Mohamed Trebak
Keyword(s):  
Annual Review ◽  
Publication Date ◽  
Loss Of Function ◽  
Physiological Functions ◽  
Crac Channels ◽  
Evolutionarily Conserved ◽  
Crac Channel ◽  
Neuronal Systems ◽  
Pore Forming Proteins ◽  
Shed Light

Store-operated Ca2+ entry (SOCE) is a ubiquitous Ca2+ signaling pathway that is evolutionarily conserved across eukaryotes. SOCE is triggered physiologically when the endoplasmic reticulum (ER) Ca2+ stores are emptied through activation of inositol-1,4,5-trisphosphate receptors. SOCE is mediated by the Ca2+ release-activated Ca2+ (CRAC) channels, which are highly Ca2+ selective. Upon store depletion, the ER Ca2+-sensing STIM proteins aggregate and gain extended conformations spanning the ER-plasma membrane junctional space to bind and activate Orai, the pore-forming proteins of hexameric CRAC channels. In recent years, studies on STIM and Orai tissue-specific knockout mice and gain- and loss-of-function mutations in humans have shed light on the physiological functions of SOCE in various tissues. Here, we describe recent findings on the composition of native CRAC channels and their physiological functions in immune, muscle, secretory, and neuronal systems to draw lessons from transgenic mice and human diseases caused by altered CRAC channel activity. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Immunosensation: Neuroimmune Cross Talk in the Skin

2021 ◽  
Vol 39 (1) ◽  
Author(s):  
Masato Tamari ◽  
Aaron M. Ver Heul ◽  
Brian S. Kim
Keyword(s):  
Immune System ◽  
Host Immunity ◽  
The Body ◽  
Annual Review ◽  
Publication Date ◽  
Protective Behaviors ◽  
Evolutionarily Conserved ◽  
Structural Barrier ◽  
Thermal Stimuli ◽  
Antimicrobial Immunity

Classically, skin was considered a mere structural barrier protecting organisms from a diversity of environmental insults. In recent decades, the cutaneous immune system has become recognized as a complex immunologic barrier involved in both antimicrobial immunity and homeostatic processes like wound healing. To sense a variety of chemical, mechanical, and thermal stimuli, the skin harbors one of the most sophisticated sensory networks in the body. However, recent studies suggest that the cutaneous nervous system is highly integrated with the immune system to encode specific sensations into evolutionarily conserved protective behaviors. In addition to directly sensing pathogens, neurons employ novel neuroimmune mechanisms to provide host immunity. Therefore, given that sensation underlies various physiologies through increasingly complex reflex arcs, a much more dynamic picture is emerging of the skin as a truly systemic organ with highly coordinated physical, immunologic, and neural functions in barrier immunology. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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.

Paligenosis: Cellular Remodeling During Tissue Repair

2021 ◽  
Vol 84 (1) ◽  
Author(s):  
Jeffrey W. Brown ◽  
Charles J. Cho ◽  
Jason C. Mills
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Tissue Repair ◽  
Annual Review ◽  
Publication Date ◽  
Cell Plasticity ◽  
Evolutionarily Conserved ◽  
Single Cell Rna Sequencing ◽  
Multicellular Organisms ◽  
New Framework

Complex multicellular organisms have evolved specific mechanisms to replenish cells in homeostasis and during repair. Here, we discuss how emerging technologies (e.g., single-cell RNA sequencing) challenge the concept that tissue renewal is fueled by unidirectional differentiation from a resident stem cell. We now understand that cell plasticity, i.e., cells adaptively changing differentiation state or identity, is a central tissue renewal mechanism. For example, mature cells can access an evolutionarily conserved program (paligenosis) to reenter the cell cycle and regenerate damaged tissue. Most tissues lack dedicated stem cells and rely on plasticity to regenerate lost cells. Plasticity benefits multicellular organisms, yet it also carries risks. For one, when long-lived cells undergo paligenotic, cyclical proliferation and redifferentiation, they can accumulate and propagate acquired mutations that activate oncogenes and increase the potential for developing cancer. Lastly, we propose a new framework for classifying patterns of cell proliferation in homeostasis and regeneration, with stem cells representing just one of the diverse methods that adult tissues employ. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

A Tale of Two Checkpoints: ATR Inhibition and PD-(L)1 Blockade

2021 ◽  
Vol 73 (1) ◽  
Author(s):  
Natalie Y.L. Ngoi ◽  
Guang Peng ◽  
Timothy A. Yap
Keyword(s):  
Ataxia Telangiectasia ◽  
Innate Immune ◽  
Annual Review ◽  
Publication Date ◽  
Checkpoint Activation ◽  
Cycle Arrest ◽  
Specific Effects ◽  
Damage Response ◽  
Shed Light

Innate immunity and the DNA damage response (DDR) pathway are inextricably linked. Within the DDR, ataxia telangiectasia and Rad3-related (ATR) is a key kinase responsible for sensing replication stress and facilitating DNA repair through checkpoint activation, cell cycle arrest, and promotion of fork recovery. Recent studies have shed light on the immunomodulatory role of the ATR-CHK1 pathway in the tumor microenvironment and the specific effects of ATR inhibition in stimulating an innate immune response. With several potent and selective ATR inhibitors in developmental pipelines, the combination of dual ATR and PD-(L)1 blockade has attracted increasing interest in cancer therapy. In this review, we summarize the clinical and preclinical data supporting the combined inhibition of ATR and PD-(L)1, discuss the potential challenges surrounding this approach, and highlight biomarkers relevant for selected patients who are most likely to benefit from the blockade of these two checkpoints. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Domestic Pressure and International Climate Cooperation

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Alessandro Tavoni ◽  
Ralph Winkler
Keyword(s):  
Climate Change ◽  
Empirical Literature ◽  
Annual Review ◽  
Environmental Agreements ◽  
Publication Date ◽  
International Policy ◽  
International Climate Policy ◽  
Important Challenge ◽  
International Climate ◽  
Shed Light

In the wake of 25 United Nations Climate Change Conferences of the Parties (and counting), international cooperation on mitigating greenhouse gas emissions to avoid substantial and potentially irreversible climate change remains an important challenge. The limited impact of the Kyoto Protocol on curbing emissions, and the gap between the ambitions of its successor and the Paris Agreement's lack of sanctioning mechanisms for addressing noncompliance, demonstrates both the difficulties in negotiating ambitious environmental agreements and the reluctance of countries to comply with their agreed emission targets once they have joined the treaty. Therefore, a better understanding of the obstacles and opportunities that the interactions between domestic and international policy pose for the design of successful international climate cooperation is of utmost importance. To shed light on the roots of the stalemate (and suggest possible ways out), this article reviews and draws lessons from a growing theoretical, experimental, and empirical literature that accounts for the hierarchical interplay between domestic political pressure and international climate policy. Expected final online publication date for the Annual Review of Resource Economics, Volume 13 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Dynamic Nutrient Signaling Networks in Plants

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Lei Li ◽  
Kun-hsiang Liu ◽  
Jen Sheen
Keyword(s):  
Plant Biomass ◽  
Metabolic Reprogramming ◽  
Signaling Networks ◽  
Annual Review ◽  
Publication Date ◽  
Cellular Mechanisms ◽  
Growth And Survival ◽  
Coordinate Gene Expression ◽  
Evolutionarily Conserved ◽  
Nutrient Signaling

Nutrients are vital to life through intertwined sensing, signaling, and metabolic processes. Emerging research focuses on how distinct nutrient signaling networks integrate and coordinate gene expression, metabolism, growth, and survival. We review the multifaceted roles of sugars, nitrate, and phosphate as essential plant nutrients in controlling complex molecular and cellular mechanisms of dynamic signaling networks. Key advances in central sugar and energy signaling mechanisms mediated by the evolutionarily conserved master regulators HEXOKINASE1 (HXK1), TARGET OF RAPAMYCIN (TOR), and SNF1-RELATED PROTEIN KINASE1 (SNRK1) are discussed. Significant progress in primary nitrate sensing, calcium signaling, transcriptome analysis, and root–shoot communication to shape plant biomass and architecture are elaborated. Discoveries on intracellular and extracellular phosphate signaling and the intimate connections with nitrate and sugar signaling are examined. This review highlights the dynamic nutrient, energy, growth, and stress signaling networks that orchestrate systemwide transcriptional, translational, and metabolic reprogramming, modulate growth and developmental programs, and respond to environmental cues. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 37 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Integration of Multimodal Data for Deciphering Brain Disorders

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jingqi Chen ◽  
Guiying Dong ◽  
Liting Song ◽  
Xingzhong Zhao ◽  
Jixin Cao ◽  
...  
Keyword(s):  
Human Brain ◽  
Data Science ◽  
Annual Review ◽  
Publication Date ◽  
Biomedical Data ◽  
Brain Disorders ◽  
Multimodal Data ◽  
Future Data ◽  
The Brain ◽  
Shed Light

The accumulation of vast amounts of multimodal data for the human brain, in both normal and disease conditions, has provided unprecedented opportunities for understanding why and how brain disorders arise. Compared with traditional analyses of single datasets, the integration of multimodal datasets covering different types of data (i.e., genomics, transcriptomics, imaging, etc.) has shed light on the mechanisms underlying brain disorders in greater detail across both the microscopic and macroscopic levels. In this review, we first briefly introduce the popular large datasets for the brain. Then, we discuss in detail how integration of multimodal human brain datasets can reveal the genetic predispositions and the abnormal molecular pathways of brain disorders. Finally, we present an outlook on how future data integration efforts may advance the diagnosis and treatment of brain disorders. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 4 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Epithelial Stem and Progenitor Cells in Lung Repair and Regeneration

2020 ◽  
Vol 83 (1) ◽  
Author(s):  
Konstantinos-Dionysios Alysandratos ◽  
Michael J. Herriges ◽  
Darrell N. Kotton
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Annual Review ◽  
Publication Date ◽  
Lung Epithelium ◽  
Lung Epithelial ◽  
Stem And Progenitor Cells ◽  
Mammalian Lung ◽  
Shed Light

The mammalian lung epithelium is composed of a wide array of specialized cells that have adapted to survive environmental exposure and perform the tasks necessary for respiration. Although the majority of these cells are remarkably quiescent during adult lung homeostasis, a growing body of literature has demonstrated the capacity of these epithelial lineages to proliferate in response to injury and regenerate lost or damaged cells. In this review, we focus on the regionally distinct lung epithelial cell types that contribute to repair after injury, and we address current controversies regarding whether elite stem cells or frequent facultative progenitors are the predominant participants. We also shed light on the newly emerging approaches for exogenously generating similar lung epithelial lineages from pluripotent stem cells. Expected final online publication date for the Annual Review of Physiology, Volume 83 is February 10, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

CRISPR Screens to Identify Regulators of Tumor Immunity

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Martin W. LaFleur ◽  
Arlene H. Sharpe
Keyword(s):  
Cancer Biology ◽  
Unmet Need ◽  
Immune Checkpoint Blockade ◽  
Annual Review ◽  
Publication Date ◽  
Loss Of Function ◽  
Technological Advances ◽  
Wide Range ◽  
Tumor Types ◽  
Cancer Immunotherapies

Cancer immunotherapies, such as immune checkpoint blockade (ICB), have been used in a wide range of tumor types with immense clinical benefit. However, ICB does not work in all patients, and attempts to combine ICB with other immune-based therapies have not lived up to their initial promise. Thus, there is a significant unmet need to discover new targets and combination therapies to extend the benefits of immunotherapy to more patients. Systems biology approaches are well suited for addressing this problem because these approaches enable evaluation of many gene targets simultaneously and ranking their relative importance for a phenotype of interest. As such, loss-of-function CRISPR screens are an emerging set of tools being used to prioritize gene targets for modulating pathways of interest in tumor and immune cells. This review describes the first screens performed to discover cancer immunotherapy targets and the technological advances that will enable next-generation screens. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Polyelectrolyte Complex Coacervates: Recent Developments and New Frontiers

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Artem M. Rumyantsev ◽  
Nicholas E. Jackson ◽  
Juan J. de Pablo
Keyword(s):  
Polyelectrolyte Complex ◽  
Materials Science ◽  
Annual Review ◽  
Publication Date ◽  
Polymer Complex ◽  
Macroscopic Structure ◽  
Recent Developments ◽  
Thermodynamics And Dynamics ◽  
Macromolecular Architecture ◽  
Shed Light

Polyelectrolyte complex coacervates represent a wide class of materials with applications ranging from coatings and adhesives to pharmaceutical technologies. They also underpin multiple biological processes, which are only now beginning to be deciphered. The means by which molecular-scale architecture propagates into macroscopic structure, thermodynamics, and dynamics in complex coacervates is of central concern in physics, chemistry, biology, and materials science. How does polyion charge sequence dictate thermodynamic behavior? How does one tailor rheology or interfacial tension using macromolecular architecture? What emergent functionality from polymer complex coacervates has biological consequences? Recent developments in coacervate science shed light on many of these issues and raise exciting new challenges for the close integration of theory, simulations, and experiment. Expected final online publication date for the Annual Review of Condensed Matter Physics, Volume 12 is March 10, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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