Extracellular ʜ ᴄ ᴏ3̅ is sensed by mouse cerebral arteries: Regulation of tone by receptor protein tyrosine phosphatase γ

Boedtkjer, Ebbe; Hansen, Kristoffer Berg; Boedtkjer, Donna Briggs; Aalkjær, Christian; Boron, Walter F.

doi:10.1177/0271678x15610787

Cited by 42 publications

(94 citation statements)

References 36 publications

(73 reference statements)

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“…The molecular mechanisms through which H + concentrations are sensed involve changes in the structure of titratable groups with a pKa in the physiological range (ie histidine, but also other groups may be relevant due to effects of the specific environment on the pKa values) and hence of the protein structure and properties . Extracellular acid/base sensors (Figure , right side) include bona fide acid/base receptors such as (i) H + ‐sensing G‐protein‐coupled receptors (GPCRs), which have been assigned a role in extracellular acid‐induced increases in [Ca 2+ ] i and activation of extracellular signal‐regulated kinase (ERK), and (ii) the receptor protein tyrosine phosphatase‐γ (RPTPγ), a proposed alkali sensor, responding to extracellular CO 2 /

{HCO}_{3}^{-}

. Additionally, the affinity of multiple other receptors for their ligands is affected by pH changes in the physiological range, rendering them indirect H + sensors.…”

Section: Signalling Mechanisms Linking Ph To Cell Proliferationmentioning

confidence: 99%

Roles of pH in control of cell proliferation

2018

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Precise spatiotemporal regulation of intracellular pH (pH ) is a prerequisite for normal cell function, and changes in pH or pericellular pH (pH ) exert important signalling functions. It is well established that proliferation of mammalian cells is dependent on a permissive pH in the slightly alkaline range (7.0-7.2). It is also clear that mitogen signalling in nominal absence of HCO3- is associated with an intracellular alkalinization (~0.3 pH unit above steady-state pH ), which is secondary to activation of Na /H exchange. However, it remains controversial whether this increase in pH is part of the mitogenic signal cascade leading to cell cycle entry and progression, and whether it is relevant under physiological conditions. Furthermore, essentially all studies of pH in mammalian cell proliferation have focused on the mitogen-induced G0-G1 transition, and the regulation and roles of pH during the cell cycle remain poorly understood. The aim of this review is to summarize and critically discuss the possible roles of pH and pH in cell cycle progression. While the focus is on the mammalian cell cycle, important insights from studies in lower eukaryotes are also discussed. We summarize current evidence of links between cell cycle progression and pH and discuss possible pH - and pH sensors and signalling pathways relevant to mammalian proliferation control. The possibility that changes in pH during cell cycle progression may be an integral part of the checkpoint control machinery is explored. Finally, we discuss the relevance of links between pH and proliferation in the context of the perturbed pH homoeostasis and acidic microenvironment of solid tumours.

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{HCO}_{3}^{-}

. Additionally, the affinity of multiple other receptors for their ligands is affected by pH changes in the physiological range, rendering them indirect H + sensors.…”

Section: Signalling Mechanisms Linking Ph To Cell Proliferationmentioning

confidence: 99%

Roles of pH in control of cell proliferation

2018

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“…Contactins 3−6, also expressed on neurons, interact with the CALD RPTPγ, which is also expressed in neurons (Bouyain & Watkins, 2010), an example of a neuron-neuron interaction. Recent reports suggest that RPTPγ is a CO 2 /HCO 3 sensor (Boedtkjer et al 2016;Zhou et al 2016).…”

Section: Communication Between Neurons and Astrocytesmentioning

confidence: 99%

Role of Cl⁻–HCO₃⁻ exchanger AE3 in intracellular pH homeostasis in cultured murine hippocampal neurons, and in crosstalk to adjacent astrocytes

Salameh

Hübner

Boron

2016

The Journal of Physiology

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Key pointsr A polymorphism of human AE3 is associated with idiopathic generalized epilepsy. Knockout of AE3 in mice lowers the threshold for triggering epileptic seizures. The explanations for these effects are elusive. r AE3 speeds re-alkalization after removal of MAc in neurons and astrocytes, and speeds neuronal pH i recovery from an ammonium prepulse-induced acid load.r We propose that neuronal AE3 indirectly increases acid extrusion in (a) neurons via Cl -loading, and (b) astrocytes by somehow enhancing NBCe1 (major acid extruder). The latter would enhance depolarization-induced alkalinization of astrocytes, and extracellular acidification, and thereby reduce susceptibility to epileptic seizures. AbstractThe anion exchanger AE3, expressed in hippocampal (HC) neurons but not astrocytes, contributes to intracellular pH (pH i ) regulation by facilitating the exchange of extracellular Cl -for intracellular HCO 3 -. The human AE3 polymorphism A867D is associated with idiopathic generalized epilepsy. Moreover, AE3 knockout (AE3 -/-) mice are more susceptible to epileptic seizure. The mechanism of these effects has been unclear because the starting pH i in AE3 -/-and wild-type neurons is indistinguishable. The purpose of the present study was to use AE3 -/-mice to investigate the role of AE3 in pH i homeostasis in HC neurons, co-cultured with astrocytes. We find that the presence of AE3 increases the acidification rate constant during pH i recovery from intracellular alkaline loads imposed by reducing [CO 2 ]. The presence of AE3 also speeds intracellular acidification during the early phase of metabolic acidosis (MAc), not just in neurons but, surprisingly, in adjacent astrocytes. Additionally, AE3 contributes to braking the decrease in pH i later during MAc in both neurons and astrocytes. Paradoxically, AE3 enhances intracellular re-alkalization after MAc removal in neurons and astrocytes, and pH i recovery from an ammonium prepulse-induced acid load in neurons. The effects of AE3 knockout on astrocytic pH i homeostasis in MAc-related assays require the presence of neurons, and are consistent with the hypothesis that the AE3 knockout reduces functional expression of astrocytic NBCe1. These findings suggest a new type of neuron-astrocyte communication, based on the expression of AE3 in neurons, which could explain how AE3 reduces seizure susceptibility.

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“…Recent reports of the interesting role of receptor protein tyrosine phosphatase‐γ in sensing extracellular CO 2 /HCO 3 − in the renal proximal tubules and cerebral arteries (Boedtkjer et al . ; Zhou et al . ) may provide important directives for future work in tumour cells.…”

Section: General Introductionmentioning

confidence: 99%

Hypoxia and cellular metabolism in tumour pathophysiology

Parks

Cormerais

Pouysségur

2017

The Journal of Physiology

118

104

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Adaptation and expansion Developing Tumour Demand SupplyProduction Clearance N u t r i e n t s / e n e r g y M e t a b o l i c w a s t e Hypoxia Abstract Cancer cells are optimised for growth and survival via an ability to outcompete normal cells in their microenvironment. Many of these advantageous cellular adaptations are promoted Scott Parks' work has focused on cellular membrane-transport physiology, first during his PhD at the University of Alberta on aquatic organisms with Dr Greg Goss, followed by transitioning to France to work with Dr Jacques Pouysségur on hypoxia and tumour cell metabolism initially at the University of Nice and now at the Centre Scientifique de Monaco. Yann Cormerais has recently completed his PhD in the Pouysségur lab in Monaco where he has become an expert in tumour amino-acid control pathways and mTOR signalling. Jacques Pouysségur obtained his PhD in 1972 on bacterial genetics at the University of Lyon followed by a two year postdoc at the National Cancer Institute of the NIH. He established his research group in 1978 at the CNRS Biochemistry Centre of the University of Nice. After directing the CNRS ISDBC institute (1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008), his team joined the IRCAN institute in Nice and the Centre Scientifique de Monaco. His research has spanned the areas of bacterial and somatic cell genetics, Na + /H + exchange, pH regulation, G protein-coupled receptors and MAP kinase signalling in the context of growth control in mammalian cells. His group has been interested for the last 15 years in hypoxia signalling, angiogenesis, cancer metabolism, nutrient sensing and amino-acid transport.This review was presented at the symposium "Physiological gases in health and disease", which took place at Physiology 2016, Dublin, Ireland, 29-31 July 2016. by the pathophysiological hypoxia that arises in solid tumours due to incomplete vascularisation. Tumour cells are thus faced with the challenge of an increased need for nutrients to support the drive for proliferation in the face of a diminished extracellular supply. Among the many modifications occurring in tumour cells, hypoxia inducible factors (HIFs) act as essential drivers of key pro-survival pathways via the promotion of numerous membrane and cytosolic proteins.Here we focus our attention on two areas: the role of amino acid uptake and the handling of metabolic acid (CO 2 /H + ) production. We provide evidence for a number of hypoxia-induced proteins that promote cellular anabolism and regulation of metabolic acid-base levels in tumour cells including amino-acid transporters (LAT1), monocarboxylate transporters, and acid-base regulating carbonic anhydrases (CAs) and bicarbonate transporters (NBCs). Emphasis is placed on current work manipulating multiple CA isoforms and NBCs, which is at an interesting crossroads of gas physiology as they are regulated by hypoxia to contribute to the cellular handling of CO 2 and pH i regulation. Our research combined with others indicates that targeting of ...

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Extracellular ʜ ᴄ ᴏ3̅ is sensed by mouse cerebral arteries: Regulation of tone by receptor protein tyrosine phosphatase γ

Abstract: We investigate sensing and signaling mechanisms for H þ , HCO

Cited by 42 publications

References 36 publications

Roles of pH in control of cell proliferation

Roles of pH in control of cell proliferation

Role of Cl⁻–HCO₃⁻ exchanger AE3 in intracellular pH homeostasis in cultured murine hippocampal neurons, and in crosstalk to adjacent astrocytes

Hypoxia and cellular metabolism in tumour pathophysiology

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Extracellular ʜ ᴄ ᴏ3̅ is sensed by mouse cerebral arteries: Regulation of tone by receptor protein tyrosine phosphatase γ

Abstract: We investigate sensing and signaling mechanisms for H þ , HCO

Cited by 42 publications

References 36 publications

Roles of pH in control of cell proliferation

Roles of pH in control of cell proliferation

Role of Cl−–HCO3− exchanger AE3 in intracellular pH homeostasis in cultured murine hippocampal neurons, and in crosstalk to adjacent astrocytes

Hypoxia and cellular metabolism in tumour pathophysiology

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Role of Cl⁻–HCO₃⁻ exchanger AE3 in intracellular pH homeostasis in cultured murine hippocampal neurons, and in crosstalk to adjacent astrocytes