Non-Neuronal Functions of the M2 Muscarinic Acetylcholine Receptor

Ockenga, Wymke; Kühne, Sina; Bocksberger, Simone; Banning, Antje; Tikkanen, Ritva

doi:10.3390/genes4020171

Cited by 26 publications

(23 citation statements)

References 168 publications

(202 reference statements)

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“…MAPK signaling has been reported to be the major downstream signaling of histamine and muscarinic receptor signaling (Ockenga et al, 2013). Similarly to naive mES cells, MAPK signaling activities were downregulated in mEPS cells (Figure S7E).…”

Section: Resultsmentioning

confidence: 99%

Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency

Yang

Liu

et al. 2017

Cell

411

469

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SUMMARY Of all known cultured stem cell types, pluripotent stem cells (PSCs) sit atop the landscape of developmental potency and are characterized by their ability to generate all cell types of an adult organism. However, PSCs show limited contribution to the extraembryonic placental tissues in vivo. Here, we show that a chemical cocktail enables the derivation of stem cells with unique functional and molecular features from mice and humans, designated as extended pluripotent stem (EPS) cells, which are capable of chimerizing both embryonic and extraembryonic tissues. Notably, a single mouse EPS cell shows widespread chimeric contribution to both embryonic and extraembryonic lineages in vivo and permits generating single-EPS-cell-derived mice by tetraploid complementation. Furthermore, human EPS cells exhibit interspecies chimeric competency in mouse conceptuses. Our findings constitute a first step toward capturing pluripotent stem cells with extraembryonic developmental potentials in culture and open new avenues for basic and translational research.

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Section: Resultsmentioning

confidence: 99%

Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency

Yang

Liu

et al. 2017

Cell

411

469

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“…We first used carbachol, a muscarinic receptor agonist that specifically acts on mammalian host cells and stimulates Ca 2+ oscillations (17). Muscarinic receptors, stimulated by the neurotransmitter acetylcholine, are well-characterized G-coupled protein receptors that lead to an increase in cytosolic Ca 2+ via activation of a phosphatidyl inositol phospholipase C (PI-PLC) and generation of inositol 1,4,5-trisphosphate (IP3) (18). Carbachol addition resulted in a dramatic rise in the fluorescence of RGECO or jRGECO1a, indicating an increase in host cytosolic Ca 2+ ( Fig 1A, red tracings).…”

Section: Calcium Influx In Intracellular Parasitesmentioning

confidence: 99%

The Role of Potassium and Host Calcium Signaling inToxoplasma gondiiegress

Vella

Moore

et al. 2020

Preprint

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Toxoplasma gondii, an obligate intracellular parasite, is capable of invading virtually any nucleated cell. Active invasion by the parasite is a precise process and intracellular parasites reside and replicate inside a parasitophorous vacuole (PV). The membrane of the PV functions as a molecular sieve allowing for its ionic milieu to be in equilibrium with the host cytosol. The parasite would thus be exposed to the ionic fluctuations of the host cytoplasm, such as increases in host cytosolic Ca 2+ during Ca 2+ signaling events. Ca 2+ is a universal signaling molecule and both the host cell and T. gondii will utilize Ca 2+ signaling to stimulate diverse cellular functions. Using T. gondii tachyzoites and host cells expressing genetically encoded Ca 2+ indicators, we demonstrate that host Ca 2+ signaling impacts intracellular Ca 2+ levels of the parasite. We propose that Ca 2+ influx derived from host Ca 2+ signaling into the parasite is utilized to maintain the intracellular Ca 2+ stores replenished as the parasite replicates within the low Ca 2+ environment of the host cell.Intracellular Ca 2+ store(s) release is needed to reach the initiation spike in Ca 2+ that meets the threshold of Ca 2+ needed to initiate the tightly coordinated process of egress. Post activation of the signal and subsequent microneme secretion, would cause breakdown of the host cell and allow for extracellular Ca 2+ influx, causing a second, larger spike in Ca 2+ and activation of the glideosome, the main motility machinery. To directly deliver precise concentrations of ions needed for egress, we used patch-clamped infected host cells and monitored parasite egress. In doing so, we discovered an alternative role for K + in timing parasite egress. This is the first study using wholecell patch clamp to study the role of ions such as K + and Ca 2+ in T. gondii egress. Author SummaryToxoplasma gondii is an intracellular parasite that causes disease by engaging in multiple rounds of a lytic cycle which consists of invasion, replication inside a parasitophorous vacuole (PV) and egress, resulting in lysis of the host cell. In intracellular parasites, the release of Ca 2+ from intracellular stores forms part of a series of signaling events that culminate in stimulation of motility and egress. This means that intracellular parasites must be able to uptake Ca 2+ while replicating to keep their intracellular stores filled to be used during egress. This is not an insignificant task considering that they are inside a PV surrounded by the host cytosol which contains Ca 2+ below 100 nM. We present data showing that the host Ca 2+ increases are able to 3 reach the parasite cytosol through a Ca 2+ influx mechanism sensitive to nifedipine. This influx causes oscillations that are the result of Ca 2+ increase and re-uptake by intracellular stores. A Ca 2+ threshold was needed for egress, extracellular Ca 2+ influx was relevant for egress and potassium had a modulatory effect on egress. We used infected patched host cells, a novel approach that leaves the host ...

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“…The five subtypes of mAChRs (designated as M 1 to M 5 ) transmit their signals mainly by means of heterotrimeric G proteins, which can be either inhibitory, resulting in reduced cyclic AMP amounts, or stimulatory, inducing a release of second messengers such as inositol 3,4,5-trisphosphate or diacylglycerol. Further downstream of these canonical signaling pathways, various protein kinases are activated that then regulate the function of numerous target molecules (for a review, see [ 4 ]).…”

Section: Introductionmentioning

confidence: 99%

Cholinergic Transactivation of the EGFR in HaCaT Keratinocytes Stimulates a Flotillin-1 Dependent MAPK-Mediated Transcriptional Response

Kühne

Ockenga

Banning

et al. 2015

IJMS

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Acetylcholine and its receptors regulate numerous cellular processes in keratinocytes and other non-neuronal cells. Muscarinic acetylcholine receptors are capable of transactivating the epidermal growth factor receptor (EGFR) and, downstream thereof, the mitogen-activated protein kinase (MAPK) cascade, which in turn regulates transcription of genes involved in cell proliferation and migration. We here show that cholinergic stimulation of human HaCaT keratinocytes results in increased transcription of matrix metalloproteinase MMP-3 as well as several ligands of the epidermal growth factor family. Since both metalloproteinases and the said ligands are involved in the transactivation of the EGFR, this transcriptional upregulation may provide a positive feed-forward loop for EGFR/MAPK activation. We here also show that the cholinergic EGFR and MAPK activation and the upregulation of MMP-3 and EGF-like ligands are dependent on the expression of flotillin-1 which we have previously shown to be a regulator of MAPK signaling.

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Non-Neuronal Functions of the M2 Muscarinic Acetylcholine Receptor

Cited by 26 publications

References 168 publications

Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency

Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency

The Role of Potassium and Host Calcium Signaling inToxoplasma gondiiegress

Cholinergic Transactivation of the EGFR in HaCaT Keratinocytes Stimulates a Flotillin-1 Dependent MAPK-Mediated Transcriptional Response

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