receptor biology
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Livers ◽  
2022 ◽  
Vol 2 (1) ◽  
pp. 15-29
Author(s):  
Emilio Flint ◽  
Evangelos Triantafyllou ◽  
Christine Bernsmeier

TAM receptors (Tyro3, Axl and MerTK) are a family of tyrosine kinase receptors that are expressed in a variety of cell populations, including liver parenchymal and non-parenchymal cells. These receptors are vital for immune homeostasis, as they regulate the innate immune response by suppressing inflammation via toll-like receptor inhibition and by promoting tissue resolution through efferocytosis. However, there is increasing evidence indicating that aberrant TAM receptor signaling may play a role in pathophysiological processes in the context of liver disease. This review will explore the roles of TAM receptors and their ligands in liver homeostasis as well as a variety of disease settings, including acute liver injury, steatosis, fibrosis, cirrhosis-associated immune dysfunction and hepatocellular carcinoma. A better understanding of our current knowledge of TAM receptors in liver disease may identify new opportunities for disease monitoring as well as novel therapeutic targets. Nonetheless, this review also aims to highlight areas where further research on TAM receptor biology in liver disease is required.


Author(s):  
Valeriya Pankova ◽  
Khin Thway ◽  
Robin L. Jones ◽  
Paul H. Huang

Soft tissue sarcomas are rare cancers of mesenchymal origin or differentiation comprising over 70 different histological subtypes. Due to their mesenchymal differentiation, sarcomas are thought to produce and deposit large quantities of extracellular matrix (ECM) components. Interactions between ECM ligands and their corresponding adhesion receptors such as the integrins and the discoidin domain receptors play key roles in driving many fundamental oncogenic processes including uncontrolled proliferation, cellular invasion and altered metabolism. In this review, we focus on emerging studies that describe the key ECM components commonly found in soft tissue sarcomas and discuss preclinical and clinical evidence outlining the important role that these proteins and their cognate adhesion receptors play in sarcomagenesis. We conclude by providing a perspective on the need for more comprehensive in-depth analyses of both the ECM and adhesion receptor biology in multiple histological subtypes in order to identify new drug targets and prognostic biomarkers for this group of rare diseases of unmet need.


2021 ◽  
Vol 22 (23) ◽  
pp. 13153
Author(s):  
Alyssa Schledwitz ◽  
Margaret H. Sundel ◽  
Madeline Alizadeh ◽  
Shien Hu ◽  
Guofeng Xie ◽  
...  

Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers.


2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tuzim Kamila ◽  
Korolczuk Agnieszka

AbstractBitter taste-sensing type 2 receptors (TAS2Rs or T2Rs), belonging to the subgroup of family A G-protein coupled receptors (GPCRs), are of crucial importance in the perception of bitterness. Although in the first instance, TAS2Rs were considered to be exclusively distributed in the apical microvilli of taste bud cells, numerous studies have detected these sensory receptor proteins in several extra-oral tissues, such as in pancreatic or ovarian tissues, as well as in their corresponding malignancies. Critical points of extra-oral TAS2Rs biology, such as their structure, roles, signaling transduction pathways, extensive mutational polymorphism, and molecular evolution, have been currently broadly studied. The TAS2R cascade, for instance, has been recently considered to be a pivotal modulator of a number of (patho)physiological processes, including adipogenesis or carcinogenesis. The latest advances in taste receptor biology further raise the possibility of utilizing TAS2Rs as a therapeutic target or as an informative index to predict treatment responses in various disorders. Thus, the focus of this review is to provide an update on the expression and molecular basis of TAS2Rs functions in distinct extra-oral tissues in health and disease. We shall also discuss the therapeutic potential of novel TAS2Rs targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles.


2021 ◽  
Vol 2 ◽  
pp. 17
Author(s):  
Rita Singh ◽  
Divya Mehul ◽  
Gordhan Singh ◽  
Rohit Kumar ◽  
Smita Bhatia

Coronavirus disease 2019 (COVID-19) became a pandemic due to a high rate of infection by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2). People with comorbidities such as cardiovascular diseases, Type II diabetes, and COPD have been having acute symptoms and higher rate of mortality. Further, increased severity and lethality of SARS-CoV-2 infection has been observed among men than in women. SARSCoV-2 infects human cells by binding to angiotensin-converting enzyme 2 (ACE2) through its spike protein (S-Protein). ACE2 is a critical transmembrane protein of the renin-angiotensin-aldosterone system which modulates the cardiovascular system and fluid homeostasis. This article reviews the current knowledge about the mechanisms of sex-based differences that may cause variations in COVID-19 susceptibility and outcomes among males and females. Males have been shown to have a delayed viral clearance due to increased retention of coronavirus as compared to females. Recent studies indicate that a severe infection with SARS-CoV-2 impairs spermatogenesis in males, however, the mechanisms by which SARS-CoV-2 damages testicular cells need more studies. We discuss here the distinctive features such as sex hormone milieu, receptor biology, and immunology that may be responsible for the gender-based differences in the outcome of COVID-19.


Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1517
Author(s):  
Eleonora Pauletto ◽  
Nils Eickhoff ◽  
Nuno A. Padrão ◽  
Christine Blattner ◽  
Wilbert Zwart

The tripartite motif (TRIM) protein family is attracting increasing interest in oncology. As a protein family based on structure rather than function, a plethora of biological activities are described for TRIM proteins, which are implicated in multiple diseases including cancer. With hormone-driven cancers being among the leading causes of cancer-related death, TRIM proteins have been described to portrait tumor suppressive or oncogenic activities in these tumor types. This review describes the biological impact of TRIM proteins in relation to hormone receptor biology, as well as hormone-independent mechanisms that contribute to tumor cell biology in prostate, breast, ovarian and endometrial cancer. Furthermore, we point out common functions of TRIM proteins throughout the group of hormone-driven cancers. An improved understanding of the biological impact of TRIM proteins in cancer may pave the way for improved prognostication and novel therapeutics, ultimately improving cancer care for patients with hormone-driven cancers.


Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 470
Author(s):  
Shampa Ghosh ◽  
Jitendra Kumar Sinha ◽  
Tarab Khan ◽  
Kuramkote Shivanna Devaraju ◽  
Prabhakar Singh ◽  
...  

Epilepsy affects around 50 million people across the globe and is the third most common chronic brain disorder. It is a non-communicable disease of the brain that affects people of all ages. It is accompanied by depression, anxiety, and substantially increased morbidity and mortality. A large number of third-generation anti-epileptic drugs are available, but they have multiple side-effects causing a decline in the quality of life. The inheritance and etiology of epilepsy are complex with multiple underlying genetic and epigenetic mechanisms. Different neurotransmitters play intricate functions to maintain the normal physiology of various neurons. If there is any dysregulation of neurotransmission due to aberrant transmitter levels or their receptor biology, it can result in seizures. In this review, we have discussed the roles played by various neurotransmitters and their receptors in the pathophysiology of epilepsy. Drug-resistant epilepsy (DRE) has remained one of the forefront areas of epilepsy research for a long time. Understanding the mechanisms underlying DRE is of utmost importance because of its high incidence rate among epilepsy patients and increased risks of psychosocial problems and premature death. Here we have enumerated various hypotheses of DRE. Further, we have discussed different non-conventional therapeutic strategies, including combination therapy and non-drug treatment. The recent studies supporting the modern approaches for the treatment of epilepsy have been deliberated with particular reference to the mTOR pathway, breakdown of the blood-brain barrier, and inflammatory pathways.


2020 ◽  
pp. jbc.RA120.014726
Author(s):  
Yujing Sun ◽  
Daolai Zhang ◽  
Ming-Liang Ma ◽  
Hui Lin ◽  
Youchen Song ◽  
...  

The adhesion GPCR ADGRG2, also known as GPR64, is a critical regulator of male fertility that maintains ion/pH homeostasis and CFTR coupling. The molecular basis of ADGRG2 function is poorly understood, in part due to the fact that no endogenous ligands for ADGRG2 have been reported, thus limiting the tools available to interrogate ADGRG2 activity. It has been shown that ADGRG2 can be activated by a peptide, termed p15, derived from its own N-terminal region known as the Stachel sequence. However, the low affinity of p15 limits its utility for ADGRG2 characterization. In the current study, we used alanine scanning mutagenesis to examine the critical residues responsible for p15-induced ADGRG2 activity. We next designed systematic strategies to optimize the peptide agonist of ADGRG2, using natural and unnatural amino acid substitutions. We obtained an optimized ADGRG2 Stachel peptide T1V/F3Phe(4-Me) (VPM-p15) that activated ADGRG2 with significantly improved (>2 orders of magnitude) affinity. We then characterized the residues in ADGRG2 that were important for ADGRG2 activation in response to VPM-p15 engagement, finding that the toggle switch W6.53 and residues of ECL2 region of ADGRG2 are key determinants for VPM-p15 interactions and VPM-p15 induced Gs or arrestin signaling. Our study not only provides a useful tool to investigate the function of ADGRG2, but also offers new insights to guide further optimization of Stachel peptides to activate adhesion GPCR members.


Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1929
Author(s):  
Malte Sgodda ◽  
Susanne Alfken ◽  
Axel Schambach ◽  
Reto Eggenschwiler ◽  
Pawel Fidzinski ◽  
...  

Synthetic receptor biology and genome editing are emerging techniques, both of which are currently beginning to be used in preclinical and clinical applications. We were interested in whether a combination of these techniques approaches would allow for the generation of a novel type of reporter cell that would recognize transient cellular events through specifically designed synthetic receptors and would permanently store information about these events via associated gene editing. Reporting cells could be used in the future to detect alterations in the cellular microenvironment, including degenerative processes or malignant transformation into cancer cells. Here, we explored synthetic Notch (synNotch) receptors expressed in human embryonic kidney cells to investigate the efficacy of antigen recognition events in a time- and dose-dependent manner. First, we evaluated the most suitable conditions for synNotch expression based on dsRed-Express fluorophore expression. Then, we used a synNotch receptor coupled to transcriptional activators to induce the expression of a Cas9 nuclease targeted to a specific genomic DNA site. Our data demonstrate that recognition of various specific antigens via synNotch receptors robustly induced Cas9 expression and resulted in an indel formation frequency of 34.5%–45.5% at the targeted CXCR4 locus. These results provide proof of concept that reporter cells can be designed to recognize a given event and to store transient information permanently in their genomes.


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