Regulation of G protein‐coupled receptor signaling by plasma membrane organization and endocytosis

Weinberg, Zara Y.; Puthenveedu, Manojkumar A.

doi:10.1111/tra.12628

Cited by 68 publications

(48 citation statements)

References 116 publications

(229 reference statements)

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“…Next, we addressed the CME downstream intracellular mechanism leading to YAP1 cytoplasmic redistribution and transcriptional reprogramming. Active endocytosis not only regulates PM SA in cells, but is also essential for controlling the surface distribution of a wide-range of membrane proteins including surface receptors and transporters (Antonescu et al, 2014;Bokel and Brand, 2014;Weinberg and Puthenveedu, 2018). Recent studies have suggested that surface expression of glucose transporters and the levels of cytoplasmic glucose can control YAP1 localization and activity (Santinon et al, 2015;Zhang et al, 2018).…”

Section: Increased Cme Upon Cell Fusion Results In Transient Glucose mentioning

confidence: 99%

Transcriptional reprogramming in fused cells is triggered by plasma-membrane diminution

Feliciano

Espinosa-Medina

Weigel

et al. 2019

Preprint

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Developing cells divide and differentiate, and in many tissues, such as bone, muscle, and placenta, cells fuse acquiring specialized functions. While it is known that fused-cells are differentiated, it is unclear what mechanisms trigger the programmatic-change, and whether cell-fusion alone drives differentiation. To address this, we employed a fusogen-mediated cell-fusion system involving undifferentiated cells in tissue culture. RNA-seq analysis revealed cell-fusion initiates a dramatic transcriptional change towards differentiation. Dissecting the mechanisms causing this reprogramming, we observed that after cell-fusion plasma-membrane surface area decreases through increased endocytosis. Consequently, glucose-transporters are internalized, and cytoplasmic-glucose and ATP transiently decrease. This low-energetic state activates AMPK, which inhibits YAP1, causing cell-cycle arrest. Impairing either endocytosis or AMPK prevents YAP1 inhibition and cell-cycle arrest after fusion. Together these data suggest that cell-fusion-induced differentiation does not need to rely on extrinsiccues; rather the plasma-membrane diminishment forced by the geometrictransformations of cell-fusion cause transient cell-starvation that induces differentiation. GLUCOSE [GLUC] AMPK [ATP] YAP1 NON-FUSED CELLS PROLIFERATIVE STATE Proliferation genes GLUCOSE [GLUC] [ATP] YAP1-P SYNCYTIUM DIFFERENTIATED STATE Differentiation genes GLUCOSE [GLUC] AMPK [ATP] LOW ENERGY STATE / REMODELING YAP1 CME Proliferation genes CELL FUSION Figure 8. Feliciano et al.

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Section: Increased Cme Upon Cell Fusion Results In Transient Glucose mentioning

confidence: 99%

Transcriptional reprogramming in fused cells is triggered by plasma-membrane diminution

Feliciano

Espinosa-Medina

Weigel

et al. 2019

Preprint

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“…TyrRII has previously been shown to be broadly responsive to a variety of monoamines and, given that monoamine release is generally associated with arousal [46][47][48][49], this system could represent an elegant mechanism for astrocytes to track wakefulness and consequently homeostatic sleep need. Because monoaminergic receptor expression is often tightly regulated by diverse signaling mechanisms [50], we examined whether tyrRII expression varied according to sleep need. We assessed astrocyte expression of tyrRII mRNA using TRAP-qPCR (Translating Ribosome Affinity Purification followed by Quantitative PCR) [51], which we performed by expressing eGFP-RpL10a in astrocytes and immunopurifying actively translating mRNA using magnetic beads coated with anti-GFP antibodies ( Figure 5A).…”

Section: Tyrrii Is Upregulated With Sleep Loss and Participates In A mentioning

confidence: 99%

Astroglial Calcium Signaling Encodes Sleep Need in Drosophila

Blum

Keleş

Baz

et al. 2020

Preprint

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SUMMARYSleep is under homeostatic control, whereby increasing wakefulness generates sleep need and triggers sleep drive. However, the molecular and cellular pathways by which sleep need is encoded are poorly understood. In addition, the mechanisms underlying both how and when sleep need is transformed to sleep drive are unknown. Here, using ex vivo and in vivo imaging, we show in Drosophila that astroglial Ca2+ signaling increases with sleep need. We demonstrate that this signaling is dependent on a specific L-type Ca2+ channel and is required for homeostatic sleep rebound. Thermogenetically increasing Ca2+ in astrocytes induces persistent sleep behavior, and we exploit this phenotype to conduct a genetic screen for genes required for the homeostatic regulation of sleep. From this large-scale screen, we identify TyrRII, a monoaminergic receptor required in astrocytes for sleep homeostasis. TyrRII levels rise following sleep deprivation in a Ca2+-dependent manner, promoting further increases in astrocytic Ca2+ and resulting in a positive-feedback loop. These data suggest that TyrRII acts as a gate to enable the transformation of sleep need to sleep drive at the appropriate time. Moreover, our findings suggest that astrocytes then transmit this sleep need to the R5 sleep drive circuit, by upregulation and release of the interleukin-1 analog Spätzle. These findings define astroglial Ca2+ signaling mechanisms encoding sleep need and reveal dynamic properties of the sleep homeostatic control system.

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“…i) Endosomal involvement: The importance of GPCR signaling from endosomal/intracellular compartments (Hanyaloglu 2018;Weinberg et a, 2019), needs to be understood in depth so that appropriate therapeutic targets can be designed.…”

Section: Supplementarymentioning

confidence: 99%

Sustained exposure to trypsin causes cells to transition into a state of reversible stemness that is amenable to transdifferentiation

Sharma

Kumar

Sharma

et al. 2019

Preprint

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During cell culture, trypsin, a serine protease, is applied to cells for 5-10 minutes to separate them from each other and from the underlying substratum so that they can be transferred to a different vessel, for re-plating, after growth medium containing 10 % serum has been added to the cells, in a well-known technique known as 'passaging'. The serum in the growth medium contains alpha-1 antitrypsin, which is a potent inhibitor of trypsin, elastase and other serine proteases.Although what is used is bovine serum in which levels of proteins could be different from levels seen in humans, normal human serum contains A1AT (> 1 mg/ml; > ~18 µmol/L) as well as trypsin itself (< 460 ng/ml, or ~0.02 µmol/L), with the former in a ~900-fold molar excess over the latter. Thus, it may be assumed there is also enough A1AT in the bovine serum added during passaging, to neutralize the trypsin (~100 μM) present in the small volume of trypsin-EDTA solution used to separate cells. What are the consequences of not adding serum, when growth medium is added, or of maintaining cells for a few tens of hours in the presence of trypsin, in a serum-free growth medium? What does such sustained exposure to trypsin during cell culture do to cells? More generally, what are the responses of cells within an organism to the balance of trypsin and A1AT in the serum that bathes them constantly? We know that excesses and deficiencies in the levels of either trypsin or A1AT are associated with disease. We know that cellular metabolism can be influenced through signaling involving protease activated membrane GPCR receptors (PAR1-4). In particular, we know of a receptor called PAR2, which is specifically activated by trypsin, expressed by cells at baseline levels, and upregulated through some feedback involving trypsin-activation. We also know that cells at sites of injury or inflammation produce and secrete trypsin, and that this trypsin can act locally upon cells in a variety of ways, all of which have probably not yet been elucidated. Here, we show that sustained exposure to trypsin induces cells to de-differentiate into a stem-like state. We show that if serum is either not added at all, or added and then washed away (after confluency is attained), during cell culture, all cells exposed to exogenously-added trypsin undergo changes in morphology, transcriptome, secretome, and developmental potential, and transition into a state of stemness, in minimal essential medium (MEM). Regardless of their origins, i.e., independent of whether they are derived from primary cultures, cell lines or cancer cell lines, and regardless of the original cell type used, exposure to trypsin (~10 µM; ~250 µg/ml) at a concentration 10-fold lower than that used to separate cells during passaging (~100 μM), over a period of 24-48 hours, causes cells to (1) become rounded, (2) cluster together, (3) get arrested in the G0/G1 stage of the cell cycle, (4) display increased presence of 5-hydroxymethyl cytosine in their nuclei (indicative of reprogramming), (5) display increased...

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Regulation of G protein‐coupled receptor signaling by plasma membrane organization and endocytosis

Cited by 68 publications

References 116 publications

Transcriptional reprogramming in fused cells is triggered by plasma-membrane diminution

Transcriptional reprogramming in fused cells is triggered by plasma-membrane diminution

Astroglial Calcium Signaling Encodes Sleep Need in Drosophila

Sustained exposure to trypsin causes cells to transition into a state of reversible stemness that is amenable to transdifferentiation

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