Targeting GRK5 for Treating Chronic Degenerative Diseases

G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors and they are responsible for the transduction of extracellular signals, regulating almost all aspects of mammalian physiology. These receptors are specifically regulated by a family of serine/threonine kinases, called GPCR kinases (GRKs). Given the biological role of GPCRs, it is not surprising that GRKs are also involved in several pathophysiological processes. Particular importance is emerging for GRK5, which is a multifunctional protein, expressed in different cell types, and it has been found located in single or multiple subcellular compartments. For instance, when anchored to the plasma membrane, GRK5 exerts its canonical function, regulating GPCRs. However, under certain conditions (e.g., pro-hypertrophic stimuli), GRK5 translocates to the nucleus of cells where it can interact with non-GPCR-related proteins as well as DNA itself to promote “non-canonical” signaling, including gene transcription. Importantly, due to these actions, several studies have demonstrated that GRK5 has a pivotal role in the pathogenesis of chronic-degenerative disorders. This is true in the cardiac cells, tumor cells, and neurons. For this reason, in this review article, we will inform the readers of the most recent evidence that supports the importance of targeting GRK5 to prevent the development or progression of cancer, cardiovascular, and neurological diseases.

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Therapeutic Exosomes in Prognosis and Developments of Coronary Artery Disease

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.691548 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ai-Qun Chen ◽

Xiao-Fei Gao ◽

Zhi-Mei Wang ◽

Feng Wang ◽

Shuai Luo ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Cell Types ◽

Biological Functions ◽

Stent Restenosis ◽

Artery Disease ◽

Almost All ◽

Different Cell Types ◽

Insight Into ◽

Systematic Knowledge

Exosomes, with an diameter of 30~150 nm, could be released from almost all types of cells, which contain diverse effective constituent, such as RNAs, proteins, lipids, and so on. In recent years, exosomes have been verified to play an important role in mechanism, diagnosis, treatment, and prognosis of cardiovascular disease, especially coronary artery disease (CAD). Moreover, it has also been shown that exosomes derived from different cell types have various biological functions based on the cell stimulation and microenvironment. However, therapeutic exosomes are currently far away from clinical translation, despite it is full of hope. In this review, we summarize an update of the recent studies and systematic knowledge of therapeutic exosomes in atherosclerosis, myocardial infarction, and in-stent restenosis, which might provide a novel insight into the treatment of CAD and promote the potential clinical application of therapeutic exosomes.

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The complement of desmosomal plaque proteins in different cell types.

The Journal of Cell Biology ◽

10.1083/jcb.101.4.1442 ◽

1985 ◽

Vol 101 (4) ◽

pp. 1442-1454 ◽

Cited By ~ 122

Author(s):

P Cowin ◽

H P Kapprell ◽

W W Franke

Keyword(s):

Guinea Pig ◽

Cell Types ◽

Cardiac Cells ◽

Myocardial Tissue ◽

Cell Type ◽

Wide Range ◽

Specific Manner ◽

A Cell ◽

Cell Type Specific ◽

Different Cell Types

Desmosomal plaque proteins have been identified in immunoblotting and immunolocalization experiments on a wide range of cell types from several species, using a panel of monoclonal murine antibodies to desmoplakins I and II and a guinea pig antiserum to desmosomal band 5 protein. Specifically, we have taken advantage of the fact that certain antibodies react with both desmoplakins I and II, whereas others react only with desmoplakin I, indicating that desmoplakin I contains unique regions not present on the closely related desmoplakin II. While some of these antibodies recognize epitopes conserved between chick and man, others display a narrow species specificity. The results show that proteins whose size, charge, and biochemical behavior are very similar to those of desmoplakin I and band 5 protein of cow snout epidermis are present in all desmosomes examined. These include examples of simple and pseudostratified epithelia and myocardial tissue, in addition to those of stratified epithelia. In contrast, in immunoblotting experiments, we have detected desmoplakin II only among cells of stratified and pseudostratified epithelial tissues. This suggests that the desmosomal plaque structure varies in its complement of polypeptides in a cell-type specific manner. We conclude that the obligatory desmosomal plaque proteins, desmoplakin I and band 5 protein, are expressed in a coordinate fashion but independently from other differentiation programs of expression such as those specific for either epithelial or cardiac cells.

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Review: Intracardiac intracellular angiotensin system in diabetes

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00512.2011 ◽

2012 ◽

Vol 302 (5) ◽

pp. R510-R517 ◽

Cited By ~ 45

Author(s):

Rajesh Kumar ◽

Qian Chen Yong ◽

Candice M. Thomas ◽

Kenneth M. Baker

Keyword(s):

Mechanism Of Action ◽

Treatment Strategies ◽

Renin Angiotensin System ◽

Cell Types ◽

Local System ◽

Cardiac Cells ◽

Angiotensin System ◽

Pathological Conditions ◽

Cardiac Pathophysiology ◽

Different Cell Types

The renin-angiotensin system (RAS) has mainly been categorized as a circulating and a local tissue RAS. A new component of the local system, known as the intracellular RAS, has recently been described. The intracellular RAS is defined as synthesis and action of ANG II intracellularly. This RAS appears to differ from the circulating and the local RAS, in terms of components and the mechanism of action. These differences may alter treatment strategies that target the RAS in several pathological conditions. Recent work from our laboratory has demonstrated significant upregulation of the cardiac, intracellular RAS in diabetes, which is associated with cardiac dysfunction. Here, we have reviewed evidence supporting an intracellular RAS in different cell types, ANG II's actions in cardiac cells, and its mechanism of action, focusing on the intracellular cardiac RAS in diabetes. We have discussed the significance of an intracellular RAS in cardiac pathophysiology and implications for potential therapies.

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Exosomes and cardiovascular cell–cell communication

Essays in Biochemistry ◽

10.1042/ebc20170081 ◽

2018 ◽

Vol 62 (2) ◽

pp. 193-204 ◽

Cited By ~ 14

Author(s):

Adam J. Poe ◽

Anne A. Knowlton

Keyword(s):

Biological Fluids ◽

Cell Communication ◽

Cell Types ◽

Cardiac Cells ◽

The Body ◽

Biologically Active ◽

Surrounding Tissue ◽

Intercellular Signaling ◽

Cardiac Damage ◽

Almost All

Exosomes have become an important player in intercellular signaling. These lipid microvesicles can stably transfer miRNA, protein, and other molecules between cells and circulate throughout the body. Exosomes are released by almost all cell types and are present in most if not all biological fluids. The biologically active cargo carried by exosomes can alter the phenotype of recipient cells. Exosomes increasingly are recognized as having an important role in the progression and treatment of cardiac disease states. Injured cardiac cells can release exosomes with important pathological effects on surrounding tissue, in addition to effecting other organs. But of equal interest is the possible benefit(s) conferred by exosomes released from stem cells for use in treatment and possible repair of cardiac damage.

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Direct linkage of thrombin to its cell surface receptors in different cell types

Journal of Supramolecular Structure ◽

10.1002/jss.400120209 ◽

1979 ◽

Vol 12 (2) ◽

pp. 245-257 ◽

Cited By ~ 17

Author(s):

Robert L. Simmer ◽

Joffre B. Baker ◽

Dennis D. Cunningham

Keyword(s):

Cell Surface ◽

Cell Types ◽

Cell Surface Receptors ◽

Surface Receptors ◽

Direct Linkage ◽

Different Cell Types

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Turnover of the carboxy-terminal tyrosine of alpha-tubulin and means of reaching elevated levels of detyrosination in living cells

Journal of Cell Science ◽

10.1242/jcs.88.2.185 ◽

1987 ◽

Vol 88 (2) ◽

pp. 185-203

Author(s):

J. Wehland ◽

K. Weber

Keyword(s):

Primary Cultures ◽

Neuroblastoma Cells ◽

Cell Types ◽

Morphological Transformation ◽

Alpha Tubulin ◽

Tubulin Antibodies ◽

Cell Processes ◽

Carboxy Terminal ◽

Almost All ◽

Different Cell Types

Monoclonal antibodies specific for either the tyrosinated (Tyr) or the detyrosinated (Glu) form of alpha-tubulin were elicited with synthetic peptides spanning the carboxy-terminal sequences of the two forms. While almost all microtubules (MTs) are usually of the Tyr-tubulin type (Tyr-rich MTs) some MTs containing noticeable amounts of Glu-tubulin (Glu-rich MTs) were found in many but not all cell lines studied. Glu-rich MTs seemed absent from proliferating CHO and N115 neuroblastoma cells. When differentiation of these cells was initiated by the addition of forskolin for CHO, or by serum deprivation for N115, elevated levels of microtubular Glu-tubulin were observed. In differentiated N115 cells Glu-tubulin was restricted to MT of elongated cell processes and was not found in growth cones and many MT of the cell body. Elevated levels of Glu-tubulin were also characteristic of other differentiated cell types, including neurones and myotubes but were not found in glial cells, astrocytes and fibroblasts in the same primary cultures. Additional experiments suggested that the restricted distribution of Glu-tubulin is the result of MT subsets with different stabilities. Results with mitotic drugs indicated that detyrosination occurs on MTs rather than on soluble tubulin and that stabilization of MTs usually favours the detyrosination process. Evidence for a functional alpha-tubulin cycle involving an inherent carboxypeptidase and a recharging ligase was apparent in 3T3 cells from the preponderance of Glu-rich MTs induced by taxol treatment or the micro-injection of certain antibodies either protecting the detyrosinated form (Glu-tubulin antibodies) or inhibiting retyrosination (ligase antibodies). As the same treatment of CHO cells resulted in comparable arrays of Glu-rich MTs only when forskolin was also present, different cell types may differ in the level of active carboxypeptidase. The results are discussed in terms of possible functions of the tyrosination/detyrosination cycle of alpha-tubulin. While most results can be explained on the basis of ‘older’ and, consequently, more detyrosinated MTs, others raise the possibility that cyclic-AMP-dependent events and certain environmental influences known to induce either a morphological transformation or a differentiation event may influence the carboxypeptidase inherent in the alpha-tubulin cycle.

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Expression of acid-base-related proteins in mesonephric kidney of the rabbit

AJP Renal Physiology ◽

10.1152/ajprenal.1994.267.6.f987 ◽

1994 ◽

Vol 267 (6) ◽

pp. F987-F997 ◽

Cited By ~ 1

Author(s):

T. Matsumoto ◽

C. A. Winkler ◽

L. P. Brion ◽

G. J. Schwartz

Keyword(s):

Collecting Duct ◽

Cell Types ◽

Intercalated Cells ◽

Acid Base ◽

Principal Cells ◽

Collecting Tubule ◽

Metanephric Kidney ◽

Collecting Tubules ◽

Related Proteins ◽

Different Cell Types

The mesonephric kidney, precursor to the metanephric kidney, comprises 30-50 nephrons, each with a glomerulus and proximal, distal, and collecting tubules. Although two different cell types have been identified in the mesonephric collecting tubule, no relationship to cells of the metanephric collecting duct has been established. To characterize expression of some of the acid-base-related proteins, we assayed for carbonic anhydrase (CA) activity and performed immunocytochemistry in mesonephroi from 15- to 20-day-old fetal rabbits. From total RNA, we detected expression of CA II and CA IV mRNA. Microdissected proximal and collecting tubules abundantly expressed both CA II and CA IV, at least to the extent observed in mature metanephric proximal tubules and collecting ducts. Histochemistry confirmed the expression of CA activity in these segments; in the collecting tubule, 28% of the collecting tubule cells were CA rich. Most CA-rich cells showed apical H(+)-ATPase and basolateral band 3 anion exchanger staining consistent with the findings in mature H(+)-secreting (alpha) intercalated cells of the metanephric collecting duct. CA-negative cells could be labeled with an antibody that identifies mature metanephric principal cells. Thus the mesonephric collecting tubule has many cells resembling mature alpha-intercalated cells and a majority of cells resembling principal cells. The similarity to the metanephric collecting duct suggests that the lineages of metanephric alpha-intercalated and principal cells may be closely related to those of the mesonephros.

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Cell Type-Selective Loss of Peroxisomal β-Oxidation Impairs Bipolar Cell but Not Photoreceptor Survival in the Retina

Cells ◽

10.3390/cells11010161 ◽

2022 ◽

Vol 11 (1) ◽

pp. 161

Author(s):

Daniëlle Swinkels ◽

Yannick Das ◽

Sai Kocherlakota ◽

Stefan Vinckier ◽

Eric Wever ◽

...

Keyword(s):

Bipolar Cell ◽

Cell Types ◽

Bipolar Cells ◽

Cell Type ◽

Peroxisomal Disorders ◽

Multifunctional Protein ◽

Ribbon Synapses ◽

Different Cell Types ◽

Oxidation Enzyme ◽

Photoreceptor Death

Retinal degeneration is a common feature in peroxisomal disorders leading to blindness. Peroxisomes are present in the different cell types of the retina; however, their precise contribution to retinal integrity is still unclear. We previously showed that mice lacking the central peroxisomal β-oxidation enzyme, multifunctional protein 2 (MFP2), develop an early onset retinal decay including photoreceptor cell death. To decipher the function of peroxisomal β-oxidation in photoreceptors, we generated cell type selective Mfp2 knockout mice, using the Crx promotor targeting photoreceptors and bipolar cells. Surprisingly, Crx-Mfp2−/− mice maintained photoreceptor length and number until the age of 1 year. A negative electroretinogram was indicative of preserved photoreceptor phototransduction, but impaired downstream bipolar cell signaling from the age of 6 months. The photoreceptor ribbon synapse was affected, containing free-floating ribbons and vesicles with altered size and density. The bipolar cell interneurons sprouted into the ONL and died. Whereas docosahexaenoic acid levels were normal in the neural retina, levels of lipids containing very long chain polyunsaturated fatty acids were highly increased. Crx-Pex5−/− mice, in which all peroxisomal functions are inactivated in photoreceptors and bipolar cells, developed the same phenotype as Crx-Mfp2−/− mice. In conclusion, the early photoreceptor death in global Mfp2−/− mice is not driven cell autonomously. However, peroxisomal β-oxidation is essential for the integrity of photoreceptor ribbon synapses and of bipolar cells.

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Platelet Toll-Like Receptors: Bridging Inflammation and Immunity

Blood ◽

10.1182/blood.v128.22.sci-45.sci-45 ◽

2016 ◽

Vol 128 (22) ◽

pp. SCI-45-SCI-45

Author(s):

Paul Kubes

Keyword(s):

Immune Cells ◽

Conflicts Of Interest ◽

Detection System ◽

Vascular Dysfunction ◽

Cell Types ◽

Neutrophil Extracellular Traps ◽

Extracellular Traps ◽

Almost All ◽

Different Cell Types

Abstract Since the discovery that there is a series of pattern recognition receptors that allow the immune system to detect pathogens, there has been a lot of work to elucidate the signaling molecules that contribute to this detection system. Although the cell types involved would seem to be just as important, our understanding of which cells are critical remains less well explored. Using intravital imaging to visualize the different cell types, we were surprised to find that in almost all conditions that we examined, platelets were rapidly recruited to afflicted tissues. Under some conditions, platelets bound vascular macrophage including Kupffer cells and helped contain bacteria. These were instantaneous responses. At later times, platelets bound neutrophils and induced the production of neutrophil extracellular traps (NETs) that helped to catch bacteria as well as viruses but did induce some local vascular injury. In some scenarios, platelets bound endothelial cells and whether this was to wall off and contain infections or a hijacking of platelets by bacteria to induce vascular dysfunction and poor perfusion remains unclear. Visualizing platelets in sterile injury also revealed important contributions to helping recruit other immune cells that help to heal. The role of the platelet as an effector in infections and inflammation will be discussed. Disclosures No relevant conflicts of interest to declare.

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Netrin-1: Focus on its role in cardiovascular physiology and atherosclerosis

JRSM Cardiovascular Disease ◽

10.1177/2048004020959574 ◽

2020 ◽

Vol 9 ◽

pp. 204800402095957

Author(s):

Vasco Claro ◽

Albert Ferro

Keyword(s):

Fetal Development ◽

Lymphatic System ◽

Foam Cell ◽

Cell Types ◽

Axonal Guidance ◽

Macrophage Differentiation ◽

Cox 2 ◽

Related Proteins ◽

Different Cell Types ◽

Cancer And Inflammation

The netrins form a family of laminin-related proteins which were first described as modulators of cell migration and axonal guidance during fetal development. Netrin-1 is the most extensively studied member of this family and, since its discovery, non-neural roles have been associated with it. Together with its receptors, DCC/neogenin and UNC5, netrin-1 has been shown to be involved in the regulation of angiogenesis, organogenesis, cancer and inflammation. An NF-κB-dependent truncated isoform of netrin-1 has also been shown to be produced in endothelial and some types of cancer cells, which both accumulates in and affects the function of the nucleus. In atherosclerosis, conflicting roles for netrin-1 have been reported on plaque progression via its receptor UNC5b. Whereas endothelial-derived netrin-1 inhibits chemotaxis of leukocytes and reduces the migration of monocytes to the atherosclerotic plaque, netrin-1 expressed by macrophages within the plaque plays a pro-atherogenic role, promoting cell survival, recruiting smooth muscle cells and inhibiting foam cell egress to the lymphatic system. In contrast, there is evidence that netrin-1 promotes macrophage differentiation to an alternative activated phenotype and induces expression of IL-4 and IL-13, while downregulate expression of IL-6 and COX-2. Further work is needed to elucidate the precise roles of the two isoforms of netrin-1 in different cell types in the context of atherosclerosis, and its potential as a putative novel therapeutic target in this disease.

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