Intracellular calcium level is an important factor influencing ion channel modulations by PLC-coupled metabotropic receptors in hippocampal neurons

Sugawara, Yuto; Echigo, Ryousuke; Kashima, Kousuke; Minami, Hanae; Watanabe, Megumi; Nishikawa, Yuiko; Muranishi, Miho; Yoneda, Mitsugu; Ohno‐Shosaku, Takako

doi:10.1016/j.brainres.2013.03.040

Cited by 6 publications

(5 citation statements)

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“…The available evidence indicates that G-protein coupled receptors (GPCR) mediate the activation of phospholipase C-β (PLCβ) leading to the formation of inositol trisphosphate (InsP 3 ) and diacylglycerol (DAG) [ 34 ]. DAG directly activates classical types of PKCs, and IP3 activates intracellular Ca 2+ [ 35 ]. Therefore, we then examined the potential involvement of PLCβ in the transactivation of EGFR using the PLC inhibitor U73122 (20 μM).…”

Section: Resultsmentioning

confidence: 99%

Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells

Zhang

et al. 2014

J Exp Clin Cancer Res

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BackgroundWe previously identified platelet-activating factor receptor (PAFR) as being overexpressed in ovarian cancer and found that its ligand PAF evoked EGFR phosphorylation using the phospho-antibody microarray. Epidermal growth factor receptor (EGFR) are also overexpressed in ovarian cancer and contribute to the growth of ovarian cancer cells. Here, we investigated the mechanisms of crosstalk between PAFR and EGFR signaling in ovarian cancer cells to further determine whether the interaction between PAFR and EGFR synergistic contribute to the progression of ovarian cancer.MethodsExpression and localization of PAFR in several ovarian cancer cell lines were assessed by Western blot, realtime-PCR and immunofluorescence. The ovarian cancer cells were stimulated with PAF or PAF and in some experiments also pharmacological inhibitors. Phosphorylation of proteins in signaling pathways were measured by Western blot. HB-EGF concentrations of the supernatant from stimulated ovarian cancer cells were measured by enzyme-linked immunosorbent assay.ResultsOur data show that PAF increases EGFR phosphorylation through PAFR in a time- and dose- dependent manner in SKOV-3 ovarian cancer cells. This transactivation is dependent on phospholipase C-β and intracellular calcium signaling. This pathway is also Src tyrosine kinase- and metalloproteinase- dependent. PAF triggers EGFR activation through the increased heparin-binding EGF-like growth factor (HB-EGF) release in metalloprotease-dependent manner. Several studies involving EGFR transactivation through G-protein coupled receptor (GPCR) have demonstrated EGFR-dependent increase in ERK1/2 phosphorylation. Yet in SKOV-3 cells, PAF treatment also increases ERK1/2 phosphorylation in a EGFR-independent manner.ConclusionsThe results suggest that in SKOV-3 ovarian cancer cells, PAF transactivates EGFR and downstream ERK pathways, thus diversifying the GPCR-mediated signal. The crosstalk between PAFR and EGFR suggests a potentially important signaling linkage between inflammatory and growth factor signaling in ovarian cancer cells.

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Section: Resultsmentioning

confidence: 99%

Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells

Zhang

et al. 2014

J Exp Clin Cancer Res

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“…ER is the predominant source of Ca 2+ in the cytoplasm; thus, the fluxes from mitochondria and other acidic organelles have not been considered (Samtleben et al, 2015). Both PLCβ and PLCδ pathways play a role in modulating the Ca 2+ activity in the cells (de Pittà et al, 2009; Matrosov et al, 2019; Sugawara et al, 2013). The Ca 2+ concentration in the ECF stays approximately constant. The neurons were assumed to be maintaining physiological conditions (not pathological).…”

Section: Methodsmentioning

confidence: 99%

“…3. Both PLCβ and PLCδ pathways play a role in modulating the Ca 2+ activity in the cells (de Pittà et al, 2009;Matrosov et al, 2019;Sugawara et al, 2013).…”

Section: Model Descriptionmentioning

confidence: 99%

A computational model to uncover the biophysical underpinnings of neural firing heterogeneity in dissociated hippocampal cultures

Dhyani,

George,

Gare

et al. 2023

Hippocampus

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Calcium (Ca2+) imaging reveals a variety of correlated firing in cultures of dissociated hippocampal neurons, pinpointing the non‐synaptic paracrine release of glutamate as a possible mediator for such firing patterns, although the biophysical underpinnings remain unknown. An intriguing possibility is that extracellular glutamate could bind metabotropic receptors linked with inositol trisphosphate (IP3) mediated release of Ca2+ from the endoplasmic reticulum of individual neurons, thereby modulating neural activity in combination with sarco/endoplasmic reticulum Ca2+ transport ATPase (SERCA) and voltage‐gated Ca2+ channels (VGCC). However, the possibility that such release may occur in different neuronal compartments and can be inherently stochastic poses challenges in the characterization of such interplay between various Ca2+ channels. Here we deploy biophysical modeling in association with Monte Carlo parameter sampling to characterize such interplay and successfully predict experimentally observed Ca2+ patterns. The results show that the neurotransmitter level at the plasma membrane is the extrinsic source of heterogeneity in somatic Ca2+ transients. Our analysis, in particular, identifies the origin of such heterogeneity to an intrinsic differentiation of hippocampal neurons in terms of multiple cellular properties pertaining to intracellular Ca2+ signaling, such as VGCC, IP3 receptor, and SERCA expression. In the future, the biophysical model and parameter estimation approach used in this study can be upgraded to predict the response of a system of interconnected neurons.

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“…This muscarinic current response was inhibited by the phospholipase C (PLC) inhibitor U73122, but not its inactive analogue U73343, indicating the involvement of PLC-coupled types of muscarinic receptors including M 1 and M 3 subtypes (Sugawara et al, 2013). In the present study, using this muscarinic current response we assessed muscarinic agonist and antagonist activities of clozapine and NDMC in intact hippocampal excitatory and inhibitory neurons.…”

Section: Introductionmentioning

confidence: 90%

“…We previously reported that in rat cultured hippocampal neurons the activation of muscarinic receptors by applying the muscarinic agonist oxotremorine M (oxo-M) decreased the steady-state outward current at -40 mV, which was attributed to inhibition of K + channels sensitive to the M-current blocker XE991 (Sugawara et al, 2013). This muscarinic current response was inhibited by the phospholipase C (PLC) inhibitor U73122, but not its inactive analogue U73343, indicating the involvement of PLC-coupled types of muscarinic receptors including M 1 and M 3 subtypes (Sugawara et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological evidence showing muscarinic agonist–antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons

et al. 2016

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antagonist darifenacin was effective in both types of neurons. Muscarinic agonist activity of NDMC was higher than that of clozapine, higher in excitatory neurons than in inhibitory neurons, sensitive to pirenzepine, and partially masked when co-applied with clozapine. Muscarinic antagonist activity of clozapine as well as NDMC was not different between excitatory and inhibitory neurons, but clozapine was more effective than NDMC.These results demonstrate that NDMC has the ability to activate native M 1 receptors expressed in hippocampal excitatory neurons, but its agonist activity might be limited in clozapine-treated patients because of the presence of excessive clozapine with muscarinic 4 antagonist activity.

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Intracellular calcium level is an important factor influencing ion channel modulations by PLC-coupled metabotropic receptors in hippocampal neurons

Abstract: Abbreviations

Cited by 6 publications

References 54 publications

Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells

Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells

A computational model to uncover the biophysical underpinnings of neural firing heterogeneity in dissociated hippocampal cultures

Electrophysiological evidence showing muscarinic agonist–antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons

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