Inositol Signaling in the Basidiomycete Fungus Schizophyllum commune

Intracellular signaling is conserved in eukaryotes to allow for response to extracellular signals and to regulate development and cellular functions. In fungi, inositol phosphate signaling has been shown to be involved in growth, sexual reproduction, and metabolic adaptation. However, reports on mushroom-forming fungi are lacking so far. In Schizophyllum commune, an inositol monophosphatase has been found up-regulated during sexual development. The enzyme is crucial for inositol cycling, where it catalyzes the last step of inositol phosphate metabolism, restoring the inositol pool from the monophosphorylated inositol monophosphate. We overexpressed the gene in this model basidiomycete and verified its involvement in cell wall integrity and intracellular trafficking. Strong phenotypes in mushroom formation and cell metabolism were evidenced by proteome analyses. In addition, altered inositol signaling was shown to be involved in tolerance towards cesium and zinc, and increased metal tolerance towards cadmium, associated with induced expression of kinases and repression of phosphatases within the inositol cycle. The presence of the heavy metals Sr, Cs, Cd, and Zn lowered intracellular calcium levels. We could develop a model integrating inositol signaling in the known signal transduction pathways governed by Ras, G-protein coupled receptors, and cAMP, and elucidate their different roles in development.

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G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigmThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y05-127 ◽

2006 ◽

Vol 84 (3-4) ◽

pp. 287-297 ◽

Cited By ~ 124

Author(s):

Fernand Gobeil ◽

Audrey Fortier ◽

Tang Zhu ◽

Michela Bossolasco ◽

Martin Leduc ◽

...

Keyword(s):

G Protein ◽

Cell Nucleus ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Cell Metabolism ◽

Hormone Secretion ◽

G Protein Coupled Receptors ◽

A Cell ◽

G Protein Coupled

G-protein-coupled receptors (GPCRs) comprise a wide family of monomeric heptahelical glycoproteins that recognize a broad array of extracellular mediators including cationic amines, lipids, peptides, proteins, and sensory agents. Thus far, much attention has been given towards the comprehension of intracellular signaling mechanisms activated by cell membrane GPCRs, which convert extracellular hormonal stimuli into acute, non-genomic (e.g., hormone secretion, muscle contraction, and cell metabolism) and delayed, genomic biological responses (e.g., cell division, proliferation, and apoptosis). However, with respect to the latter response, there is compelling evidence for a novel intracrine mode of genomic regulation by GPCRs that implies either the endocytosis and nuclear translocation of peripheral-liganded GPCR and (or) the activation of nuclearly located GPCR by endogenously produced, nonsecreted ligands. A noteworthy example of the last scenario is given by heptahelical receptors that are activated by bioactive lipoids (e.g., PGE2 and PAF), many of which may be formed from bilayer membranes including those of the nucleus. The experimental evidence for the nuclear localization and signalling of GPCRs will be reviewed. We will also discuss possible molecular mechanisms responsible for the atypical compartmentalization of GPCRs at the cell nucleus, along with their role in gene expression.

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The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Physiological Reviews ◽

10.1152/physrev.00015.2014 ◽

2015 ◽

Vol 95 (2) ◽

pp. 377-404 ◽

Cited By ~ 82

Author(s):

Priscila Y. Sato ◽

J. Kurt Chuprun ◽

Mathew Schwartz ◽

Walter J. Koch

Keyword(s):

Heart Failure ◽

G Protein ◽

Intracellular Signaling ◽

Cellular Localization ◽

Current Data ◽

Adrenergic System ◽

Cellular Functions ◽

Health And Disease ◽

Novel Therapeutic Strategies ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent β-arrestin-mediated mechanisms including phosphorylation, internalization, and either receptor degradation or resensitization. The seven-member GRK family varies in their structural composition, cellular localization, function, and mechanism of action (see sect. II). Here, we focus our attention on GRKs in particular canonical and novel roles of the GRKs found in the cardiovascular system (see sects. III and IV). Paramount to overall cardiac function is GPCR-mediated signaling provided by the adrenergic system. Overstimulation of the adrenergic system has been highly implicated in various etiologies of cardiovascular disease including hypertension and heart failure. GRKs acting downstream of heightened adrenergic signaling appear to be key players in cardiac homeostasis and disease progression, and herein we review the current data on GRKs related to cardiac disease and discuss their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure.

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Antigen Design for Successful Isolation of Highly Challenging Therapeutic Anti-GPCR Antibodies

International Journal of Molecular Sciences ◽

10.3390/ijms21218240 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8240

Author(s):

Man-Seok Ju ◽

Sang Taek Jung

Keyword(s):

Drug Targets ◽

G Protein Coupled Receptors ◽

Clinical Validation ◽

Complex Structures ◽

Therapeutic Antibodies ◽

Cellular Functions ◽

Extracellular Signals ◽

Cellular Expression ◽

Successful Isolation ◽

G Protein Coupled

G-protein-coupled receptors (GPCR) transmit extracellular signals into cells to regulate a variety of cellular functions and are closely related to the homeostasis of the human body and the progression of various types of diseases. Great attention has been paid to GPCRs as excellent drug targets, and there are many commercially available small-molecule chemical drugs against GPCRs. Despite this, the development of therapeutic anti-GPCR antibodies has been delayed and is challenging due to the difficulty in preparing active forms of GPCR antigens, resulting from their low cellular expression and complex structures. Here, we focus on anti-GPCR antibodies that have been approved or are subject to clinical trials and present various technologies to prepare active GPCR antigens that enable the isolation of therapeutic antibodies to proceed toward clinical validation.

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β-arrestin–dependent PI(4,5)P2 synthesis boosts GPCR endocytosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2011023118 ◽

2021 ◽

Vol 118 (17) ◽

pp. e2011023118

Author(s):

Seung-Ryoung Jung ◽

Yifei Jiang ◽

Jong Bae Seo ◽

Daniel T. Chiu ◽

Bertil Hille ◽

...

Keyword(s):

Plasma Membrane ◽

Intracellular Signaling ◽

Live Cells ◽

Cellular Functions ◽

Coated Pits ◽

Endocytic Machinery ◽

S 100 ◽

Phosphatidylinositol 4 ◽

Protease Activated Receptor 2 ◽

G Protein Coupled

β-arrestins regulate many cellular functions including intracellular signaling and desensitization of G protein–coupled receptors (GPCRs). Previous studies show that β-arrestin signaling and receptor endocytosis are modulated by the plasma membrane phosphoinositide lipid phosphatidylinositol-(4, 5)-bisphosphate (PI(4,5)P2). We found that β-arrestin also helped promote synthesis of PI(4,5)P2 and up-regulated GPCR endocytosis. We studied these questions with the Gq-coupled protease-activated receptor 2 (PAR2), which activates phospholipase C, desensitizes quickly, and undergoes extensive endocytosis. Phosphoinositides were monitored and controlled in live cells using lipid-specific fluorescent probes and genetic tools. Applying PAR2 agonist initiated depletion of PI(4,5)P2, which then recovered during rapid receptor desensitization, giving way to endocytosis. This endocytosis could be reduced by various manipulations that depleted phosphoinositides again right after phosphoinositide recovery: PI(4)P, a precusor of PI(4,5)P2, could be depleted at either the Golgi or the plasma membrane (PM) using a recruitable lipid 4-phosphatase enzyme and PI(4,5)P2 could be depleted at the PM using a recruitable 5-phosphatase. Endocytosis required the phosphoinositides. Knock-down of β-arrestin revealed that endogenous β-arrestin normally doubles the rate of PIP5-kinase (PIP5K) after PAR2 desensitization, boosting PI(4,5)P2-dependent formation of clathrin-coated pits (CCPs) at the PM. Desensitized PAR2 receptors were swiftly immobilized when they encountered CCPs, showing a dwell time of ∼90 s, 100 times longer than for unactivated receptors. PAR2/β-arrestin complexes eventually accumulated around the edges or across the surface of CCPs promoting transient binding of PIP5K-Iγ. Taken together, β-arrestins can coordinate potentiation of PIP5K activity at CCPs to induce local PI(4,5)P2 generation that promotes recruitment of PI(4,5)P2-dependent endocytic machinery.

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Effects of transformation with the v-src oncogene on inositol phosphate metabolism in rat-1 fibroblasts. D-myo-inositol 1,4,5,6-tetrakisphosphate is increased in v-src-transformed rat-1 fibroblasts and can be synthesized from D-myo-inositol 1,3,4-trisphosphate in cytosolic extracts

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)98597-2 ◽

1991 ◽

Vol 266 (23) ◽

pp. 15144-15153

Author(s):

R.R. Mattingly ◽

L.R. Stephens ◽

R.F. Irvine ◽

J.C. Garrison

Keyword(s):

Inositol Phosphate ◽

Phosphate Metabolism ◽

Inositol Phosphate Metabolism

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Histamine-mediated regulation of cAMP levels and inositol phosphate metabolism in isolated rabbit retina

Agents and Actions ◽

10.1007/bf02222219 ◽

1989 ◽

Vol 27 (1-2) ◽

pp. 131-134 ◽

Cited By ~ 6

Author(s):

J. Z. Nowak ◽

B. Sek ◽

B. Szkiel

Keyword(s):

Inositol Phosphate ◽

Rabbit Retina ◽

Phosphate Metabolism ◽

Inositol Phosphate Metabolism ◽

Camp Levels

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Imaging of persistent cAMP signaling by internalized G protein-coupled receptors

Journal of Molecular Endocrinology ◽

10.1677/jme-10-0014 ◽

2010 ◽

Vol 45 (1) ◽

pp. 1-8 ◽

Cited By ~ 47

Author(s):

Davide Calebiro ◽

Viacheslav O Nikolaev ◽

Martin J Lohse

Keyword(s):

G Protein ◽

Intracellular Signaling ◽

Current Model ◽

Living Cells ◽

G Protein Coupled Receptors ◽

Membrane Receptors ◽

Optical Methods ◽

Camp Signaling ◽

Gpcr Signaling ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They mediate the effects of several endogenous cues and serve as important pharmacological targets. Although many biochemical events involved in GPCR signaling have been characterized in great detail, little is known about their spatiotemporal dynamics in living cells. The recent advent of optical methods based on fluorescent resonance energy transfer allows, for the first time, to directly monitor GPCR signaling in living cells. Utilizing these methods, it has been recently possible to show that the receptors for two protein/peptide hormones, the TSH and the parathyroid hormone, continue signaling to cAMP after their internalization into endosomes. This type of intracellular signaling is persistent and apparently triggers specific cellular outcomes. Here, we review these recent data and explain the optical methods used for such studies. Based on these findings, we propose a revision of the current model of the GPCR–cAMP signaling pathway to accommodate receptor signaling at endosomes.

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Diverse effects of G-protein-coupled free fatty acid receptors on the regulation of cellular functions in lung cancer cells

Experimental Cell Research ◽

10.1016/j.yexcr.2016.03.008 ◽

2016 ◽

Vol 342 (2) ◽

pp. 193-199 ◽

Cited By ~ 18

Author(s):

Tsubasa Kita ◽

Yui Kadochi ◽

Kaede Takahashi ◽

Kaori Fukushima ◽

Eri Yamasaki ◽

...

Keyword(s):

Lung Cancer ◽

Fatty Acid ◽

Free Fatty Acid ◽

Cancer Cells ◽

G Protein ◽

Lung Cancer Cells ◽

Cellular Functions ◽

Free Fatty Acid Receptors ◽

G Protein Coupled

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Microglia in cerebral ischemia: molecular actions and interactionsThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y05-143 ◽

2006 ◽

Vol 84 (1) ◽

pp. 49-59 ◽

Cited By ~ 121

Author(s):

Aaron Y. Lai ◽

Kathryn G. Todd

Keyword(s):

Cerebral Ischemia ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Extracellular Signals ◽

Messenger Molecules ◽

Membrane Bound ◽

The Subject ◽

Survey Review ◽

Selection Of

The precise role of microglia in stroke and cerebral ischemia has been the subject of debate for a number of years. Microglia are capable of synthesizing numerous soluble and membrane-bound biomolecules, some known to be neuroprotective, some neurotoxic, whereas others have less definitive bioactivities. The molecular mechanisms through which microglia activate these molecules have thus become an important area of ischemia research. Here we provide a survey review that summarizes the key actions of microglial factors in cerebral ischemia including complement proteins, chemokines, pro-inflammatory cytokines, neurotrophic factors, hormones, and proteinases, as well several important messenger molecules that play a part in how these factors respond to extracellular signals during ischemic injuries. We also provide some new perspectives on how microglial intracellular signaling may contribute to the seemingly contradictory roles of several microglial effector molecules.

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