Tissue-specific regulation of the Na, K-ATPase by the cytosolic NaAF: some thoughts on brain function

The dual topology P-2 ATPase, which consists of a α²β² tetramer, explains numerous functions of the cation transporting ATPase system. The ubiquitous cytosolic protein regulator (NaAF) of 170 k Da mass regulates P-2 ATPase function in a low Ca (µM) neighborhood where Ca acts as the terminal regulator in the intracellular signaling cascade. The Na, K- ATPase also seems to function as an H, K-ATPase or a Ca-ATPase in altered states based on the local environment (low pH or high Ca) in a tissue specific manner. These altered effects are analogous to that of the 80 k Da cytosolic HAF in regulating the gastric H, K-ATPase system of the parietal cells. However there are some important differences. The HAF stimulates the Na, K-ATPase but the NaAF cannot stimulate H, K-ATPase. Also, HAF is as effective as NaAF in stimulating the kidney Na, K-ATPase but about 60% as effective in stimulating brain Na, K-ATPase. These observations reveal that the Na, K- ATPase systems from kidney and brain, consisting of different kinds of αβ–isoforms, interact differently with the HAF molecule; thus substantiating that P-2 ATPase system plays different roles in different tissues in response to an universal NaAF. Another rare feature of the HAF is that it has histone kinase activity, suggesting that the HAF and NaAF may be capable of sending a direct signal to the nucleus for gene expression.In this paper, the central role of the NaAF-regulated Na, K-ATPase system in the activity and function of brain tissue is discussed. It is noted that the altered function of the nerve terminus located Na, K-ATPase system works as a Ca-pump (after depolarization) and as a Na-pump (in repolarization) in alternate sequence. The possible role of Ca-sensing receptor (CaR) in the voltage gated channeling of Ca has been raised and the possibility of a dual channel Na/H antiporter (NhaA) in pH homeostasis is discussed.

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The Pleiotropic Intricacies of Hedgehog Signaling: From Craniofacial Patterning to Carcinogenesis

FACE ◽

10.1177/27325016211024326 ◽

2021 ◽

pp. 273250162110243

Author(s):

Mikhail Pakvasa ◽

Andrew B. Tucker ◽

Timothy Shen ◽

Tong-Chuan He ◽

Russell R. Reid

Keyword(s):

Intracellular Signaling ◽

Limb Development ◽

Hedgehog Signaling ◽

Target Genes ◽

Craniofacial Development ◽

Signaling Cascade ◽

Signaling Mechanisms ◽

Intracellular Signaling Cascade ◽

And Function

Hedgehog signaling was discovered more than 40 years ago in experiments demonstrating that it is a fundamental mediator of limb development. Since that time, it has been shown to be important in development, homeostasis, and disease. The hedgehog pathway proceeds through a pathway highly conserved throughout animals beginning with the extracellular diffusion of hedgehog ligands, proceeding through an intracellular signaling cascade, and ending with the activation of specific target genes. A vast amount of research has been done elucidating hedgehog signaling mechanisms and regulation. This research has found a complex system of genetics and signaling that helps determine how organisms develop and function. This review provides an overview of what is known about hedgehog genetics and signaling, followed by an in-depth discussion of the role of hedgehog signaling in craniofacial development and carcinogenesis.

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Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor

Cancers ◽

10.3390/cancers12082162 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2162

Author(s):

Mohammad Taheri ◽

Hamed Shoorei ◽

Marcel E. Dinger ◽

Soudeh Ghafouri-Fard

Keyword(s):

Estrogen Receptor ◽

G Protein ◽

Reproductive System ◽

Estrogen Regulation ◽

Tissue Specific ◽

Membrane Bound ◽

Non Coding Rnas ◽

And Function ◽

G Protein Coupled

Estrogen receptors (ERs) comprise several nuclear and membrane-bound receptors with different tissue-specific functions. ERα and ERβ are two nuclear members of this family, whereas G protein-coupled estrogen receptor (GPER), ER-X, and Gq-coupled membrane estrogen receptor (Gq-mER) are membrane-bound G protein-coupled proteins. ERα participates in the development and function of several body organs such as the reproductive system, brain, heart and musculoskeletal systems. ERβ has a highly tissue-specific expression pattern, particularly in the female reproductive system, and exerts tumor-suppressive roles in some tissues. Recent studies have revealed functional links between both nuclear and membrane-bound ERs and non-coding RNAs. Several oncogenic lncRNAs and miRNAs have been shown to exert their effects through the modulation of the expression of ERs. Moreover, treatment with estradiol has been shown to alter the malignant behavior of cancer cells through functional axes composed of non-coding RNAs and ERs. The interaction between ERs and non-coding RNAs has functional relevance in several human pathologies associated with estrogen regulation, such as cancers, intervertebral disc degeneration, coronary heart disease and diabetes. In the current review, we summarize scientific literature on the role of miRNAs and lncRNAs on ER-associated signaling and related disorders.

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The Role of Phosphotyrosine Signaling Pathway in Parotid Gland Proliferation and Function

Critical Reviews in Oral Biology & Medicine ◽

10.1177/10454411950060020201 ◽

1995 ◽

Vol 6 (2) ◽

pp. 119-131 ◽

Cited By ~ 11

Author(s):

K.R. Purushotham ◽

M.G. Humphreys-Beher

Keyword(s):

Salivary Glands ◽

Tyrosine Kinases ◽

Intracellular Signaling ◽

Potential Role ◽

Biological Processes ◽

Secretory Function ◽

Phosphotyrosine Signaling ◽

And Function ◽

Active Proliferation

Tyrosine phosphorylation and the intracellular signaling processes associated with it have been the focus of intense study due to its importance in the regulation of biological processes as diverse as cell proliferation and cell differentiation. While much of what we now understand has been derived from the study of cell lines and tumor cells, the salivary glands provide a model to examine the effects of tyrosine kinases and tyrosine phosphatases in a normal differentiated tissue. This review will focus, therefore, on the role tyrosine kinases and phosphatases play in inducing the transition from stasis to active proliferation and their potential role in mediating secretory function of the salivary glands.

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The Role of Monocytes in Gouty Arthritis

10.26686/wgtn.16959532.v1 ◽

2021 ◽

Author(s):

◽

Xiao Liu

Keyword(s):

Acute Inflammation ◽

Gouty Arthritis ◽

Local Environment ◽

Peritoneal Membrane ◽

Monocyte Chemoattractant Protein 1 ◽

Inflammatory Microenvironment ◽

Culture Techniques ◽

And Function

<p>Gout is one of the most painful forms of arthritis characterised by the deposition of monosodium urate crystals (MSU) in the joint synovium and the subsequent acute influx of circulating leukocytes. This study investigated the contribution of the inflammatory microenvironment in driving recruited monocyte differentiation and function in acute gouty inflammation. Using the murine peritoneal model of MSU-induced inflammation, the differentiation and functional phenotypes of MSU-recruited monocytes were compared in normal acute inflammation and in an inflammatory environment depleted of resident macrophages and infiltrating neutrophils. In addition, the role of the local environment in producing monocyte chemoattractant protein-1 (MCP-1) was investigated. Furthermore, the effect of transmigration on the suppressor phenotype of recruited monocytes was also explored. The pro-inflammatory environment was shown to play a key role in the differentiation and function of recruited monocytes in MSU-induced acute inflammation. In addition, infiltrating neutrophils suppressed the pro-inflammatory abilities of recruited monocytes, which may contribute to the resolution of inflammation. Using both whole peritoneal membrane preparations and in vitro culture techniques, results showed that mesothelial cells lining the peritoneal membrane were a source of MCP-1 production, which contributed to monocyte recruitment. Finally no differences were observed in either the differentiation or functional phenotypes of MSU-recruited monocytes isolated from Glatiramer acetate (GA) treated or non-treated mice. These findings suggest that the inflammatory microenvironment plays a key role in driving the recruitment, differentiation and function of circulating monocytes in the MSU-induced model of acute inflammation.</p>

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Lysosome Function in Cardiovascular Diseases

Cellular Physiology and Biochemistry ◽

10.33594/000000373 ◽

2021 ◽

Vol 55 (3) ◽

pp. 277-300

Keyword(s):

Intracellular Signaling ◽

Hydrolytic Enzymes ◽

Vascular Diseases ◽

Sphingolipid Metabolism ◽

Cellular Behavior ◽

Cellular Processes ◽

Vascular Regulation ◽

Large Numbers ◽

And Function

The lysosome is a single ubiquitous membrane-enclosed intracellular organelle with an acidic pH present in all eukaryotic cells, which contains large numbers of hydrolytic enzymes with their maximal enzymatic activity at a low pH (pH ≤ 5) such as proteases, nucleases, and phosphatases that are able to degrade extracellular and intracellular components. It is well known that lysosomes act as a center for degradation and recycling of large numbers of macromolecules delivered by endocytosis, phagocytosis, and autophagy. Lysosomes are recognized as key organelles for cellular clearance and are involved in many cellular processes and maintain cellular homeostasis. Recently, it has been shown that lysosome function and its related pathways are of particular importance in vascular regulation and related diseases. In this review, we highlighted studies that have improved our understanding of the connection between lysosome function and vascular physiological and pathophysiological activities in arterial smooth muscle cells (SMCs) and endothelial cells (ECs). Sphingolipids-metabolizingenzymes in lysosomes play critical roles in intracellular signaling events that influence cellular behavior and function in SMCs and ECs. The focus of this review will be to define the mechanism by which the lysosome contributes to cardiovascular regulation and diseases. It is believed that exploring the role of lysosomal function and its sphingolipid metabolism in the initiation and progression of vascular disease and regulation may provide novel insights into the understanding of vascular pathobiology and helps develop more effective therapeutic strategies for vascular diseases.

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The Dominant Role of Sp1 in Regulating the Cystathionine β-Synthase –1a and –1b Promoters Facilitates Potential Tissue-specific Regulation by Kruppel-like Factors

Journal of Biological Chemistry ◽

10.1074/jbc.m310211200 ◽

2003 ◽

Vol 279 (10) ◽

pp. 8558-8566 ◽

Cited By ~ 22

Author(s):

Kenneth N. Maclean ◽

Eva Kraus ◽

Jan P. Kraus

Keyword(s):

Dominant Role ◽

Tissue Specific ◽

Specific Regulation

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Monocyte Recruitment, Specification, and Function in Atherosclerosis

Cells ◽

10.3390/cells10010015 ◽

2020 ◽

Vol 10 (1) ◽

pp. 15

Author(s):

Ki-Wook Kim ◽

Stoyan Ivanov ◽

Jesse W. Williams

Keyword(s):

Live Cell Imaging ◽

Foam Cell ◽

Atherosclerotic Disease ◽

Blood Monocytes ◽

Atherosclerotic Lesions ◽

Cell Gene Expression ◽

Specific Regulation ◽

And Function ◽

Cell Gene

Atherosclerotic lesions progress through the continued recruitment of circulating blood monocytes that differentiate into macrophages within plaque. Lesion-associated macrophages are the primary immune cells present in plaque, where they take up cholesterol and store lipids in the form of small droplets resulting in a unique morphology termed foam cell. Recent scientific advances have used single-cell gene expression profiling, live-cell imaging, and fate mapping approaches to describe macrophage and monocyte contributions to pro- or anti-inflammatory mechanisms, in addition to functions of motility and proliferation within lesions. Yet, many questions regarding tissue-specific regulation of monocyte-to-macrophage differentiation and the contribution of recruited monocytes at stages of atherosclerotic disease progression remain unknown. In this review, we highlight recent advances regarding the role of monocyte and macrophage dynamics in atherosclerotic disease and identify gaps in knowledge that we hope will allow for advancing therapeutic treatment or prevention strategies for cardiovascular disease.

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Control Of Phosphoinositide Synthesis And Degradation By The Acyltransferase Lycat

10.32920/ryerson.14655252 ◽

2021 ◽

Author(s):

Yasmin Awadeh

Keyword(s):

Intracellular Signaling ◽

Critical Role ◽

Membrane Traffic ◽

New Information ◽

Selective Incorporation ◽

Lipid Kinases ◽

Membrane Compartments ◽

Epidermal Growth ◽

And Function

Phosphoinositides (PIPs) are important regulators of various cellular phenomena including intracellular signaling, membrane traffic and cell migration. PIPs are formed as a result of the regulated phosphorylation of the inositol headgroup of phosphatidylinositol (PI) on specific positions by certain lipid kinases and phosphatases. It is well appreciated that the enrichment of specific PIPs, defined by inositol headgroup phosphorylation, within specific membrane compartments plays a critical role in organelle identity and membrane traffic. However, while much attention has been given to understanding of the role of inositol headgroup phosphorylation in PIP function, much less is known about the role of dynamic incorporation of specific acyl groups into these phospholipids. Importantly, PI and PIPs exhibit remarkable and unique selectivity for certain acyl groups. For example, about 45% of PIs (but not other phospholipids) are rich in 1-steroyl 2-arachidonyl. We recently identified that the possible control of the selective incorporation of steric acid at the sn-1 position is by the acyltransferase LYCAT, which controls the levels, acyl profile and function of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) (Bone et al. Mol Biol Cell 2017. 28:161-172). Here we examine how perturbation of LYCAT leads to a reduction in the levels of PI(4,5)P2 and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3). To measure the rate of PI(4,5)P2 synthesis, we treated cells with ionomycin to first ablate this PIP, followed by washout of the drug and monitoring of rate of reappearance via localization of a fluorescent PI(4,5)P2 probe. To measure the rate of PI(4,5)P2 degradation, we arrested PI(4,5)P2 synthesis by a pharmacological inhibitor, phenylarsine oxide (PAO) and monitored the loss of cellular PI(4,5)P2. Lastly, to examine the production of PI(3,4,5)P3, we treated cells with epidermal growth factor (EGF) and monitored the production of this PIP. Together, this work provides new information about how the dynamic and selective remodeling of specific phospholipids controls their levels, localization and function.

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From syncitium to regulated pump: a cardiac muscle cellular update

AJP Advances in Physiology Education ◽

10.1152/advan.00119.2010 ◽

2011 ◽

Vol 35 (1) ◽

pp. 22-27 ◽

Cited By ~ 5

Author(s):

Donna H. Korzick

Keyword(s):

Cardiac Muscle ◽

Intracellular Signaling ◽

Ventricular Myocytes ◽

Cellular Events ◽

Intracellular Ca ◽

Health And Disease ◽

Cardiac Excitation ◽

And Function ◽

Cardiac Automaticity

The primary purpose of this article is to present a basic overview of some key teaching concepts that should be considered for inclusion in an six- to eight-lecture introductory block on the regulation of cardiac performance for graduate students. Within the context of cardiac excitation-contraction coupling, this review incorporates information on Ca2+ microdomains and local control theory, with particular emphasis on the role of Ca2+ sparks as a key regulatory component of ventricular myocyte contraction dynamics. Recent information pertaining to local Ca2+ cycling in sinoatrial nodal cells (SANCs) as a mechanism underlying cardiac automaticity is also presented as part of the recently described coupled-clock pacemaker system. The details of this regulation are emerging; however, the notion that the sequestration and release of Ca2+ from internal stores in SANCs (similar to that observed in ventricular myocytes) regulates the rhythmic excitation of the heart (i.e., membrane ion channels) is an important advancement in this area. The regulatory role of cardiac adrenergic receptors on cardiac rate and function is also included, and fundamental concepts related to intracellular signaling are discussed. An important point of emphasis is that whole organ cardiac dynamics can be traced back to cellular events regulating intracellular Ca2+ homeostasis and, as such, provides an important conceptual framework from which students can begin to think about whole organ physiology in health and disease. Greater synchrony of Ca2+-regulatory mechanisms between ventricular and pacemaker cells should enhance student comprehension of complex regulatory phenomenon in cardiac muscle.

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