Pharmacology of Adenosine Receptors: The State of the Art

Adenosine is a ubiquitous endogenous autacoid whose effects are triggered through the enrollment of four G protein-coupled receptors: A1, A2A, A2B, and A3. Due to the rapid generation of adenosine from cellular metabolism, and the widespread distribution of its receptor subtypes in almost all organs and tissues, this nucleoside induces a multitude of physiopathological effects, regulating central nervous, cardiovascular, peripheral, and immune systems. It is becoming clear that the expression patterns of adenosine receptors vary among cell types, lending weight to the idea that they may be both markers of pathologies and useful targets for novel drugs. This review offers an overview of current knowledge on adenosine receptors, including their characteristic structural features, molecular interactions and cellular functions, as well as their essential roles in pain, cancer, and neurodegenerative, inflammatory, and autoimmune diseases. Finally, we highlight the latest findings on molecules capable of targeting adenosine receptors and report which stage of drug development they have reached.

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The underground life of homeodomain-leucine zipper transcription factors

Journal of Experimental Botany ◽

10.1093/jxb/erab112 ◽

2021 ◽

Author(s):

Perotti M F ◽

Arce A L ◽

R L Chan

Keyword(s):

Transcription Factors ◽

Root Development ◽

Leucine Zipper ◽

Current Knowledge ◽

Expression Patterns ◽

Large Family ◽

Cell Types ◽

Structural Features ◽

Specific Cell ◽

High Plasticity

Abstract Roots are the anchorage organs of plants, responsible for water and nutrient uptake, exhibiting high plasticity. Root architecture is driven by the interactions of biomolecules, including transcription factors (TFs) and hormones that are crucial players regulating root plasticity. Multiple TF families are involved in root development; some, such as ARFs and LBDs, have been well characterized, whereas others remain less investigated. In this review, we synthesize the current knowledge about the involvement of the large family of homeodomain-leucine zipper (HD-Zip) TFs in root development. This family is divided into four subfamilies (I to IV), mainly according to structural features, such as additional motifs aside from HD-Zip, as well as their size, gene structure, and expression patterns. We explored and analyzed public databases and the scientific literature regarding HD-Zip TFs in Arabidopsis and other species. Most members of the four HD-Zip subfamilies are expressed in specific cell types and several ones from each group have assigned functions in root development. Notably, a high proportion of the studied proteins are part of intricate regulation pathways involved in primary and lateral root growth and development.

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Role of Septins in Endothelial Cells and Platelets

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.768409 ◽

2021 ◽

Vol 9 ◽

Author(s):

Katharina Neubauer ◽

Barbara Zieger

Keyword(s):

Endothelial Cells ◽

Higher Plants ◽

Current Knowledge ◽

Expression Patterns ◽

Cell Types ◽

Cell Junctions ◽

Specific Expression ◽

Cellular Processes ◽

Almost All

Septins are conserved cytoskeletal GTP-binding proteins identified in almost all eukaryotes except higher plants. Mammalian septins comprise 13 family members with either ubiquitous or organ- and tissue-specific expression patterns. They form filamentous oligomers and complexes with other proteins to serve as diffusions barrier and/or multi-molecular scaffolds to function in a physiologically regulated manner. Diverse septins are highly expressed in endothelial cells and platelets, which play an important role in hemostasis, a process to prevent blood loss after vascular injury. Endothelial septins are involved in cellular processes such as exocytosis and in processes concerning organismal level, like angiogenesis. Septins are additionally found in endothelial cell-cell junctions where their presence is required to maintain the integrity of the barrier function of vascular endothelial monolayers. In platelets, septins are important for activation, degranulation, adhesion, and aggregation. They have been identified as mediators of distinct platelet functions and being essential in primary and secondary hemostatic processes. Septin-knockout mouse studies show the relevance of septins in several aspects of hemostasis. This is in line with reports that dysregulation of septins is clinically relevant in human bleeding disorders. The precise function of septins in the biology of endothelial cells and platelets remains poorly understood. The following mini-review highlights the current knowledge about the role of septin cytoskeleton in regulating critical functions in these two cell types.

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Mesenchymal Stem Cell-Derived Exosomes: Applications in Regenerative Medicine

Cells ◽

10.3390/cells10081959 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1959

Author(s):

Mangesh D. Hade ◽

Caitlin N. Suire ◽

Zucai Suo

Keyword(s):

Regenerative Medicine ◽

Brain Injuries ◽

Current Knowledge ◽

Multivesicular Body ◽

Cell Types ◽

Biological Properties ◽

Cellular Functions ◽

Surface Receptors ◽

Differentiation And Proliferation ◽

Almost All

Exosomes are a type of extracellular vesicles, produced within multivesicular bodies, that are then released into the extracellular space through a merging of the multivesicular body with the plasma membrane. These vesicles are secreted by almost all cell types to aid in a vast array of cellular functions, including intercellular communication, cell differentiation and proliferation, angiogenesis, stress response, and immune signaling. This ability to contribute to several distinct processes is due to the complexity of exosomes, as they carry a multitude of signaling moieties, including proteins, lipids, cell surface receptors, enzymes, cytokines, transcription factors, and nucleic acids. The favorable biological properties of exosomes including biocompatibility, stability, low toxicity, and proficient exchange of molecular cargos make exosomes prime candidates for tissue engineering and regenerative medicine. Exploring the functions and molecular payloads of exosomes can facilitate tissue regeneration therapies and provide mechanistic insight into paracrine modulation of cellular activities. In this review, we summarize the current knowledge of exosome biogenesis, composition, and isolation methods. We also discuss emerging healing properties of exosomes and exosomal cargos, such as microRNAs, in brain injuries, cardiovascular disease, and COVID-19 amongst others. Overall, this review highlights the burgeoning roles and potential applications of exosomes in regenerative medicine.

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The Mysteries around the BCL-2 Family Member BOK

Biomolecules ◽

10.3390/biom10121638 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1638

Author(s):

Raed Shalaby ◽

Hector Flores-Romero ◽

Ana J. García-Sáez

Keyword(s):

Family Member ◽

Cell Fate ◽

Current Knowledge ◽

Structural Features ◽

Special Focus ◽

Cellular Functions ◽

Open Questions ◽

Apoptotic Protein ◽

Evolutionarily Conserved ◽

Apoptosis Regulation

BOK is an evolutionarily conserved BCL-2 family member that resembles the apoptotic effectors BAK and BAX in sequence and structure. Based on these similarities, BOK has traditionally been classified as a BAX-like pro-apoptotic protein. However, the mechanism of action and cellular functions of BOK remains controversial. While some studies propose that BOK could replace BAK and BAX to elicit apoptosis, others attribute to this protein an indirect way of apoptosis regulation. Adding to the debate, BOK has been associated with a plethora of non-apoptotic functions that makes this protein unpredictable when dictating cell fate. Here, we compile the current knowledge and open questions about this paradoxical protein with a special focus on its structural features as the key aspect to understand BOK biological functions.

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Regulation of inositol 1,4,5-trisphosphate receptors

Journal of Experimental Biology ◽

10.1242/jeb.184.1.161 ◽

1993 ◽

Vol 184 (1) ◽

pp. 161-182 ◽

Cited By ~ 1

Author(s):

I. C. Marshall ◽

C. W. Taylor

Keyword(s):

Splice Variants ◽

Divalent Cations ◽

Cell Types ◽

Smooth Muscle Contraction ◽

Receptor Activation ◽

Receptor Subtypes ◽

Inositol 1,4,5 Trisphosphate ◽

Specific Receptors ◽

Rapid Generation ◽

Allosteric Regulators

Inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] is a soluble second messenger responsible for the generation of highly organized Ca2+ signals in a variety of cell types. These Ca2+ signals control many cellular responses, including cell growth, fertilization, smooth muscle contraction and secretion. Ins(1,4,5)P3 is produced at the plasma membrane following receptor activation, but rapidly diffuses into the cytosol, where it binds to specific receptors through which it mobilizes intracellular Ca2+ stores. The actions of Ins(1,4,5)P3 within cells are tightly controlled: enzymes control the rapid generation and metabolism of Ins(1,4,5)P3 following receptor activation; multiple Ins(1,4,5)P3 receptor subtypes and splice variants exist, some of which are differentially expressed between cell types and at different stages of development; and Ins(1,4,5)P3 receptors are the targets for a number of allosteric regulators, including protein kinases, ATP and divalent cations. Understanding how cells control the Ca(2+)-mobilizing activity of Ins(1,4,5)P3 will be important if we are to unravel the mechanisms that underlie the complex arrangements of Ca2+ signals.

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Pathophysiological Role of K2P Channels in Human Diseases

Cellular Physiology and Biochemistry ◽

10.33594/000000338 ◽

2021 ◽

Vol 55 (S3) ◽

pp. 65-86

Keyword(s):

Molecular Mechanisms ◽

Current Knowledge ◽

Expression Patterns ◽

Ion Homeostasis ◽

Human Diseases ◽

Cellular Functions ◽

Aberrant Expression ◽

K2p Channels ◽

And Function

The family of two-pore domain potassium (K2P) channels is critically involved in central cellular functions such as ion homeostasis, cell development, and excitability. K2P channels are widely expressed in different human cell types and organs. It is therefore not surprising that aberrant expression and function of K2P channels are related to a spectrum of human diseases, including cancer, autoimmune, CNS, cardiovascular, and urinary tract disorders. Despite homologies in structure, expression, and stimulus, the functional diversity of K2P channels leads to heterogeneous influences on human diseases. The role of individual K2P channels in different disorders depends on expression patterns and modulation in cellular functions. However, an imbalance of potassium homeostasis and action potentials contributes to most disease pathologies. In this review, we provide an overview of current knowledge on the role of K2P channels in human diseases. We look at altered channel expression and function, the potential underlying molecular mechanisms, and prospective research directions in the field of K2P channels.

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Comprehensive Assessment of Sequence and Expression of Circular-RNAs in Progenitor Cell Types of the Developing Mammalian Cortex

10.1101/553495 ◽

2019 ◽

Author(s):

Martina Dori ◽

Leila Haj Abdullah Alieh ◽

Daniel Cavalli ◽

Simone Massalini ◽

Mathias Lesche ◽

...

Keyword(s):

Current Knowledge ◽

Expression Patterns ◽

Biological Significance ◽

Cell Types ◽

Mammalian Brain ◽

Circular Rnas ◽

Sequence Information ◽

Specific Cell ◽

Newborn Neurons ◽

And Function

ABSRTRACTCircular (circ) RNAs have recently emerged as a novel class of non coding transcripts whose identification and function remain elusive. Among many tissues and species, the mammalian brain is the organ in which circRNAs are more abundant and first evidence of their functional significance started to emerge. Yet, even within this well studied organ, annotation of circRNAs remains fragmentary, their sequence is unknown and their expression in specific cell types was never investigated. Overcoming these limitations, here we provide the fist comprehensive identification of circRNAs and their expression patterns in proliferating neural stem cells, neurogenic progenitors and newborn neurons of the developing mouse cortex. Extending the current knowledge about the diversity of this class of transcripts by the identification of nearly 4,000 new circRNAs, our study is the first to provide the full sequence information and expression patterns of circRNAs in cell types representing the lineage of neurogenic commitment. We further exploited our data by evaluating the coding potential, evolutionary conservation and biogenesis of circRNAs that we found to arise from a specific sub-class of linear mRNAs. Our study provides the arising field of circRNA biology with a powerful new resource to address the complexity and potential biological significance of this new class of transcripts.

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FFAR2/3 as Microbial Metabolite Sensors to Shape Host Health: Pharmacophysiological View

10.20944/preprints202005.0037.v1 ◽

2020 ◽

Author(s):

Sidharth P. Mishra ◽

Prashantha Karunakar ◽

Subhash Taraphder ◽

Hariom Yadav

Keyword(s):

Human Health ◽

Gut Microbiome ◽

Cell Types ◽

Short Chain Fatty Acids ◽

Structural Features ◽

Host Cells ◽

Microbial Metabolites ◽

Cellular Functions ◽

Hormone Synthesis ◽

Protein Receptors

Abstract: Role of gut microbiome in human health is becoming apparent. The major functional impact of gut microbiome is transmitted through the microbial metabolites that are produced in the gut and interact with host cells either in the local gut environment or get absorbed in the circulation to impact distant cells/organs. Short chain fatty acids (SCFAs) are the major microbial metabolites that are produced in the gut through fermentation of non-digestible fibers. SCFAs are known to function through various mechanism, however, their signaling through free-fatty acid receptor 2 and 3 (FFAR2/3; type of G-coupled protein receptors) is new therapeutic approach. FFAR2/3 are widely expression in diverse cell types in human and mice, and functions as sensors of SCFAs to change several physiological and cellular functions. FFAR2/3 modulates neurological signaling, energy metabolism, intestinal cellular homeostasis, immune response and hormone synthesis. FFAR2/3 functions through Gi and/or Gq signaling, that is mediated through specific structural features of SCFAs-FFAR2/3 bindings and modulating specific signaling pathway. In this review, we discussed the wide-spread expression and structural homologies between human and mice FFAR2/3, and their role in different human health conditions. This information can unlock opportunities to weigh the potential of FFAR2/3 as drug target to prevent human diseases.

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Tubulin heterogeneity regulates functions and dynamics of microtubules and plays a role in the development of drug resistance in cancer

Biochemical Journal ◽

10.1042/bcj20190123 ◽

2019 ◽

Vol 476 (9) ◽

pp. 1359-1376 ◽

Cited By ~ 7

Author(s):

Shweta Shyam Prassanawar ◽

Dulal Panda

Keyword(s):

Current Knowledge ◽

Cell Types ◽

Cellular Functions ◽

Spatial Cues ◽

Post Translational Modifications ◽

Tubulin Isotypes ◽

Development Of Resistance ◽

Structural And Functional Properties ◽

Differential Stability ◽

Different Cell Types

Abstract Microtubules, composed of αβ-tubulin heterodimers, exhibit diverse structural and functional properties in different cell types. The diversity in the microtubule structure originates from tubulin heterogeneities, namely tubulin isotypes and their post-translational modifications (PTMs). These heterogeneities confer differential stability to microtubules and provide spatial cues for the functioning of the cell. Furthermore, the altered expressions of tubulin isotypes and PTMs are prominent factors for the development of resistance against some cancer drugs. In this review, we summarize our current knowledge of the tubulin isotypes and PTMs and how, together, they control the cellular functions of the microtubules. We also describe how cancer cells use this tubulin heterogeneity to acquire resistance against clinical agents and discuss existing attempts to counter the developed resistance.

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Single-Cell Transcriptomics of Glioblastoma Reveals a Unique Tumor Microenvironment and Potential Immunotherapeutic Target Against Tumor-Associated Macrophage

Frontiers in Oncology ◽

10.3389/fonc.2021.710695 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaoteng Cui ◽

Qixue Wang ◽

Junhu Zhou ◽

Yunfei Wang ◽

Can Xu ◽

...

Keyword(s):

Single Cell ◽

Immune Cells ◽

Expression Profiles ◽

Expression Patterns ◽

Cell Types ◽

Marker Genes ◽

Sequencing Data ◽

Chemotherapy Drugs ◽

Categorization Scheme ◽

Almost All

BackgroundThe main immune cells in GBM are tumor-associated macrophages (TAMs). Thus far, the studies investigating the activation status of TAM in GBM are mainly limited to bulk RNA analyses of individual tumor biopsies. The activation states and transcriptional signatures of TAMs in GBM remain poorly characterized.MethodsWe comprehensively analyzed single-cell RNA-sequencing data, covering a total of 16,201 cells, to clarify the relative proportions of the immune cells infiltrating GBMs. The origin and TAM states in GBM were characterized using the expression profiles of differential marker genes. The vital transcription factors were examined by SCENIC analysis. By comparing the variable gene expression patterns in different clusters and cell types, we identified components and characteristics of TAMs unique to each GBM subtype. Meanwhile, we interrogated the correlation between SPI1 expression and macrophage infiltration in the TCGA-GBM dataset.ResultsThe expression patterns of TMEM119 and MHC-II can be utilized to distinguish the origin and activation states of TAMs. In TCGA-Mixed tumors, almost all TAMs were bone marrow-derived macrophages. The TAMs in TCGA-proneural tumors were characterized by primed microglia. A different composition was observed in TCGA-classical tumors, which were infiltrated by repressed microglia. Our results further identified SPI1 as a crucial regulon and potential immunotherapeutic target important for TAM maturation and polarization in GBM.ConclusionsWe describe the immune landscape of human GBM at a single-cell level and define a novel categorization scheme for TAMs in GBM. The immunotherapy against SPI1 would reprogram the immune environment of GBM and enhance the treatment effect of conventional chemotherapy drugs.

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