Ionotropic ATP receptors in neuronal–glial communication

doi:10.1016/j.semcdb.2011.02.012

Seminars in Cell & Developmental Biology

Volume 22, Issue 2, April 2011, Pages 220-228

https://doi.org/10.1016/j.semcdb.2011.02.012 Get rights and content

Abstract

In the central nervous system ATP is released from both neurones and astroglial cells acting as a homo- and heterocellular neurotransmitter. Glial cells express numerous purinoceptors of both ionotropic (P2X) and metabotropic (P2Y) varieties. Astroglial P2X receptors can be activated by ongoing synaptic transmission and can mediate fast local signalling through elevation in cytoplasmic Ca²⁺ and Na⁺ concentrations. These ionic signals can be translated into various physiological messages by numerous pathways, including release of gliotransmitters, metabolic support of neurones and regulation of activity of postsynaptic glutamate and GABA receptors. Ionotropic purinoceptors represent a novel pathway of glia-driven modulation of synaptic signalling that involves the release of ATP from neurones and astrocytes followed by activation of P2X receptors which can regulate synaptic activity by variety of mechanisms expressed in both neuronal and glial compartments.

Section snippets

Introduction: ATP mediated neurotransmission

The purinergic signalling system, which utilises purines (ATP, ADP and adenosine) as extracellular transmitter molecules has ancient evolutionary roots and is wide-spread throughout all life forms, from single-cell organisms to plants and animals [1], [2].

In the nervous system ATP acts as homo- (neuronal–neuronal and glial–glial) and heterocellular (neuronal–glial) neurotransmitter. In addition, ATP released from neurones and neuroglia induces a multitude of trophic effects including regulation

Quantal ATP release from neuronal terminals and astroglia

Several pathways for ATP release from undamaged neural cells have been identified in the last decade. These include concentration-gradient driven diffusion through plasmalemmal channels with large permeability (as the cytosolic concentration of ATP approaches 5–10 mM, and extracellular is set at a low nM range the resulting concentration gradient is arguably one of the highest existing in biological systems); release through ATP-binding cassette transporters and secretion by exocytosis [3], [17]

P2X receptors in the CNS

The ionotropic P2X receptors widely expressed in the brain and in the spinal cord, are ligand-gated cationic (Na⁺, K⁺ and Ca²⁺) ion channels. Functional P2X receptors are trimers; the diversity of their biophysical and pharmacological phenotype is determined by subunit composition [58]. The P2X_1–5 and P2X₇ subunits readily form homomeric receptors; the P2X₆ subunit always assembles as a part of heteromeric structure [5], [6]. The heteromeric P2X receptors described so far include P2X_1/2, P2X_1/4

Cortical astrocytes express P2X_1/5 receptors with unique ATP sensitivity

The mapping of P2X receptor expression in neuroglia is far from completion (see Butt et al., in this issue). The P2X₄ and P2X₇ receptors are functionally active in microglia [19], [63]; the P2X receptors (possibly P2X₇ receptors as well as come other, yet identified P2X subtypes) are operative in oligodendroglia [64]; P2X₁ and P2X₅ subunits were reported to be present in Schwann cells [65].

In astroglia various P2X subunits were identified at mRNA and protein levels, with differential expression

Astroglial P2X₇ receptors

The pore-forming cytolytic purinoceptor was discovered following initial observations of the cell-permeabilising effects of high concentrations ATP [70], [71]. Later the underlying ATP-gated ion channel that upon activation produces a large transmembrane pore was biophysically characterised and named the P2Z receptor [72]. The P2Z receptors were identified in various types of peripheral macrophages, lymphocytes and microglial cells [63], [73], [74].

In 1996 the molecular identity of P2Z receptor

Possible routes for P2X receptors-mediated bi-directional neuronal–glial signalling

P2X receptors, activated by ATP released from neuronal and astroglial compartments can participate in the bi-directional neuronal glial signalling through several mechanisms.

The role for astroglial P2X receptors: reporters of physiological/pathological activity?

Astroglial P2X receptors can be activated by ongoing synaptic transmission and mediate local cytoplasmic signalling mediated through [Ca²⁺]_i and [Na⁺]_i transients. Astrocytic processes enwrap the synaptic terminals forming the “functional islands” of astrocytic responsibility. Due to their high affinity, astrocytic P2X_1/5 receptors can sense the changes in the concentration of ATP in the extracellular space and therefore can monitor the activity of neural networks and adjust glial support

Acknowledgement

This work was supported by BBSRC grant BB/F0221445 to YP.

References (114)

G. Clark et al.
Extracellular nucleotides: ancient signaling molecules
Plant Sci
(2009)
F. Di Virgilio et al.
Purinergic signalling in inflammation of the central nervous system
Trends Neurosci
(2009)
Y. Pankratov et al.
P2X receptor-mediated excitatory synaptic currents in somatosensory cortex
Mol Cell Neurosci
(2003)
Y. Pankratov et al.
P2X receptors and synaptic plasticity
Neuroscience
(2009)
M.F. Jarvis
The neural-glial purinergic receptor ensemble in chronic pain states
Trends Neurosci
(2010)
G. Burnstock et al.
Vas deferens – a model used to establish sympathetic cotransmission
Trends Pharmacol Sci
(2010)
G. Queiroz et al.
Release of ATP from cultured rat astrocytes elicited by glutamate receptor activation
Neuroscience
(1997)
J.M. Zhang et al.
ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression
Neuron
(2003)
S Coco et al.
Storage and release of ATP from astrocytes in culture
J Biol Chem
(2003)
T. Pangrsic et al.
Exocytotic release of ATP from cultured astrocytes
J Biol Chem
(2007)

L.E. Browne et al.

New structure enlivens interest in P2X receptors

Trends Pharmacol Sci

(2010)

U. Lalo et al.

Ivermectin potentiates ATP-induced ion currents in cortical neurones: evidence for functional expression of P2X4 receptors?

Neurosci Lett

(2007)

S. Haas et al.

ATP-induced membrane currents in ameboid microglia acutely isolated from mouse brain slices

Neuroscience

(1996)

B. Sperlagh et al.

P2X₇ receptors in the nervous system

Prog Neurobiol

(2006)

O. Palygin et al.

Ionotropic NMDA and P2X_1/5 receptors mediate synaptically induced Ca²⁺ signalling in cortical astrocytes

Cell Calcium

(2010)

E. Rozengurt et al.

A specific effect of external ATP on the permeability of transformed 3T3 cells

Biochem Biophys Res Commun

(1975)

E. Boue-Grabot et al.

Subunit specific coupling between GABA type A and P2X₂ receptor channels

J Biol Chem

(2004)

B.K. Rycroft et al.

Inhibitory interactions of calcineurin (phosphatase 2B) and calmodulin on rat hippocampal NMDA receptors

Neuropharmacology

(2004)

M.F. Jarvis et al.

ATP-gated P2X cation-channels

Neuropharmacology

(2009)

J.L. Dutton et al.

P2X₁ receptor membrane redistribution and down-regulation visualized by using receptor-coupled green fluorescent protein chimeras

Neuropharmacology

(2000)

C. Agulhon et al.

What is the role of astrocyte calcium in neurophysiology?

Neuron

(2008)

G. Burnstock et al.

The birth and postnatal development of purinergic signalling

Acta Physiol (Oxf)

(2010)

G. Burnstock et al.

Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death

Cell Death Dis

(2010)

R.A. North

Molecular physiology of P2X receptors

Physiol Rev

(2002)

A. Surprenant et al.

Signaling at purinergic P2X receptors

Annu Rev Physiol

(2009)

A. Verkhratsky et al.

Purinoceptors on neuroglia

Mol Neurobiol

(2009)

M.P. Abbracchio et al.

International Union of Pharmacology. LVIII: Update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy

Pharmacol Rev

(2006)

B.B.I.J.A.P. Fredholm et al.

International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors

Pharmacol Rev

(2001)

D. Boison et al.

Adenosine signaling and function in glial cells

Cell Death Differ

(2010)

F.A. Edwards et al.

ATP receptor-mediated synaptic currents in the central nervous system

Nature

(1992)

Y.H. Jo et al.

Synaptic corelease of ATP and GABA in cultured spinal neurons

Nat Neurosci

(1999)

Y. Pankratov et al.

A purinergic component of the excitatory postsynaptic current mediated by P2X receptors in the CA1 neurons of the rat hippocampus

Eur J Neurosci

(1998)

Y. Pankratov et al.

Ionotropic P2X purinoreceptors mediate synaptic transmission in rat pyramidal neurones of layer II/III of somato-sensory cortex

J Physiol

(2002)

E.M. Silinsky et al.

ATP mediates excitatory synaptic transmission in mammalian neurones

Br J Pharmacol

(1992)

U. Lalo et al.

Ionotropic receptors in neuronal–astroglial signalling: what is the role of “excitable” molecules in non-excitable cells

Biochim Biophys Acta

(2010)

K. Inoue et al.

ATP receptors in pain sensation: involvement of spinal microglia and P2X₄ receptors

Purinergic Signal

(2005)

C. Agulhon et al.

Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca²⁺ signaling

Science

(2010)

J. Petravicz et al.

Loss of IP₃ receptor-dependent Ca²⁺ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity

J Neurosci

(2008)

E.B. Malarkey et al.

Mechanisms of transmitter release from astrocytes

Z. Zhang et al.

Regulated ATP release from astrocytes through lysosome exocytosis

Nat Cell Biol

(2007)

E. Scemes et al.

Connexin and pannexin mediated cell–cell communication

Neuron Glia Biol

(2007)

H.T. Liu et al.

Oxygen-glucose deprivation induces ATP release via maxi-anion channels in astrocytes

Purinergic Signal

(2008)

R.D. Fields et al.

Nonsynaptic communication through ATP release from volume-activated anion channels in axons

Sci Signal

(2010)

R.J. Thompson et al.

Ischemia opens neuronal gap junction hemichannels

Science

(2006)

Y.J. Huang et al.

The role of pannexin 1 hemichannels in ATP release and cell–cell communication in mouse taste buds

Proc Natl Acad Sci USA

(2007)

K. Sawada et al.

Identification of a vesicular nucleotide transporter

Proc Natl Acad Sci USA

(2008)

Y. Pankratov et al.

Vesicular release of ATP at central synapses

Pflugers Arch

(2006)

Y. Pankratov et al.

Quantal release of ATP in mouse cortex

J Gen Physiol

(2007)

S.J. Robertson et al.

ATP and glutamate are released from separate neurones in the rat medial habenula nucleus: frequency dependence and adenosine-mediated inhibition of release

J Physiol, Lond

(1998)

Y.H. Jo et al.

Coordinate release of ATP and GABA at in vitro synapses of lateral hypothalamic neurons

J Neurosci

(2002)

Cited by (46)

Modulation of Thalamocingulate Nociceptive Transmission and Glutamate Secretion by Targeting P2×7 Receptor
2023, Journal of Pain
The complexity and diversity of pain signaling have led to obstacles for prominent treatments due to mechanisms that are not yet fully understood. Among adenosine triphosphate (ATP) receptors, P2×7 differs in many respects from P2×1-6, it plays a significant role in various inflammatory pain, but whether it plays a role in noninflammatory pain has not been widely discussed. In this study, we utilized major neuropharmacological methods to record the effects of manipulating P2×7 during nociceptive signal transmission in the thalamocingulate circuits. Our results show that regardless of the specific cell type distribution of P2×7 in the central nervous system (CNS), it participates directly in the generated nociceptive transmission, which indicates its apparent functional existence in the major pain transmission path, the thalamocingulate circuits. Activation of P2×7 may facilitate transmission velocity along the thalamocingulate projection as well as neuron firings and synaptic vesicle release in anterior cingulate cortical neurons. Targeting thalamic P2×7 affects glutamate and ATP secretion during nociceptive signal transmission.
The observations in this study provide evidence that the ATP receptor P2×7 presents in the central ascending pain path and plays a modulatory role during nociceptive transmission, which could contribute new insights for many antinociceptive applications.
ATP-mediated signalling in the central synapses
2023, Neuropharmacology
ATP released from the synaptic terminals and astrocytes can activate neuronal P2 receptors at a variety of locations across the CNS. Although the postsynaptic ATP-mediated signalling does not bring a major contribution into the excitatory transmission, it is instrumental for slow and diffuse modulation of synaptic dynamics and neuronal firing in many CNS areas. Neuronal P2X and P2Y receptors can be activated by ATP released from the synaptic terminals, astrocytes and microglia and thereby can participate in the regulation of synaptic homeostasis and plasticity. There is growing evidence of importance of purinergic regulation of synaptic transmission in different physiological and pathological contexts. Here, we review the main mechanisms underlying the complexity and diversity of purinergic signalling and purinergic modulation in central neurons.
This article is part of the Special Issue on "Purinergic Signaling: 50 years".
The tripartite glutamatergic synapse
2021, Neuropharmacology
Astroglial cells were long considered as structural and metabolic supporting cells are which do not directly participate in information processing in the brain. Discoveries of responsiveness of astrocytes to synaptically-released glutamate and their capability to release agonists of glutamate receptors awakened extensive studies of glia-neuron communications and led to the revolutionary changes in our understanding of brain cellular networks. Nowadays, astrocytes are widely acknowledged as inseparable element of glutamatergic synapses and role for glutamatergic astrocyte-neuron interactions in the brain computation is emerging.
Astroglial glutamate receptors, in particular of NMDA, mGluR3 and mGluR5 types, can activate a variety of molecular cascades leading astroglial-driven modulation of extracellular levels of glutamate and activity of neuronal glutamate receptors. Their preferential location to the astroglial perisynaptic processes facilitates interaction of astrocytes with individual excitatory synapses. Bi-directional glutamatergic communication between astrocytes and neurons underpins a complex, spatially-distributed modulation of synaptic signalling thus contributing to the enrichment of information processing by the neuronal networks.
Still, further research is needed to bridge the substantial gaps in our understanding of mechanisms and physiological relevance of astrocyte-neuron glutamatergic interactions, in particular ability of astrocytes directly activate neuronal glutamate receptors by releasing glutamate and, arguably, d-Serine. An emerging roles for aberrant changes in glutamatergic astroglial signalling, both neuroprotective and pathogenic, in neurological and neurodegenerative diseases also require further investigation.
This article is part of the Neuropharmacology Special Issue on ‘Glutamate Receptors - The Glutamatergic Synapse’.
Calcium signaling in neuroglia
2021, International Review of Cell and Molecular Biology
Citation Excerpt :
Peripheral localized Ca2+ signals occur independently from electrical neuronal activity, but may be linked to neurotransmitter release (Di Castro et al., 2011; Panatier et al., 2011; Takata and Hirase, 2008). The spontaneous [Ca2+]i events arise from plasmalemmal Ca2+ influx because: (i) they are present in branchlets and endfeet of InsP3 receptor type 2 knockout mice; (ii) they are sensitive to inhibition of ionotropic receptors (Lalo et al., 2011; Palygin et al., 2010), TRP channels (Reyes et al., 2013; Shigetomi et al., 2013b) or NCX (Kirischuk et al., 1997; Ziemens et al., 2019); and (iii) they can be enhanced by elevation of extracellular Ca2+ (Wu et al., 2019). Additionally, Ca2+ release from flickering of the mitochondrial permeability transition pore has been suggested to contribute to spontaneous and evoked Ca2+ signals in astrocytic processes (Agarwal et al., 2017).
Glial cells exploit calcium (Ca²⁺) signals to perceive the information about the activity of the nervous tissue and the tissue environment to translate this information into an array of homeostatic, signaling and defensive reactions. Astrocytes, the best studied glial cells, use several Ca²⁺ signaling generation pathways that include Ca²⁺ entry through plasma membrane, release from endoplasmic reticulum (ER) and from mitochondria. Activation of metabotropic receptors on the plasma membrane of glial cells is coupled to an enzymatic cascade in which a second messenger, InsP₃ is generated thus activating intracellular Ca²⁺ release channels in the ER endomembrane. Astrocytes also possess store-operated Ca²⁺ entry and express several ligand-gated Ca²⁺ channels. In vivo astrocytes generate heterogeneous Ca²⁺ signals, which are short and frequent in distal processes, but large and relatively rare in soma. In response to neuronal activity intracellular and inter-cellular astrocytic Ca²⁺ waves can be produced. Astrocytic Ca²⁺ signals are involved in secretion, they regulate ion transport across cell membranes, and are contributing to cell morphological plasticity. Therefore, astrocytic Ca²⁺ signals are linked to fundamental functions of the central nervous system ranging from synaptic transmission to behavior. In oligodendrocytes, Ca²⁺ signals are generated by plasmalemmal Ca²⁺ influx, or by release from intracellular stores, or by combination of both. Microglial cells exploit Ca²⁺ permeable ionotropic purinergic receptors and transient receptor potential channels as well as ER Ca²⁺ release. In this contribution, basic morphology of glial cells, glial Ca²⁺ signaling toolkit, intracellular Ca²⁺ signals and Ca²⁺-regulated functions are discussed with focus on astrocytes.
Purinergic neurone-glia signalling in cognitive-related pathologies
2016, Neuropharmacology
Citation Excerpt :
The latter 3 types of the receptors are widely expressed in all types of glial cells (Verkhratsky et al., 2009); glial expression of P0 receptors has not yet been studied. As mentioned before, astrocytes may release a wide variety of neurotransmitters including ATP by exocytotic mechanisms involving [Ca2+]i and SNARE-proteins (Halassa and Haydon, 2010; Lalo et al., 2011c; Perea and Araque, 2010). Furthermore, ATP released from astroglia has been demonstrated to affect synaptic transmission (Newman, 2005; Pascual et al., 2005; Serrano et al., 2006; Zhang et al., 2003).
Neuroglia, represented by astrocytes, oligodendrocytes, NG glia and microglia are homeostatic, myelinating and defensive cells of the brain. Neuroglial cells express various combinations of purinoceptors, which contribute to multiple intercellular signalling pathways in the healthy and diseased nervous system. Neurological diseases are invariably associated with profound neuroglial remodelling, which is manifest by reactive gliosis, pathological remodelling and functional atrophy of various types of glial cells. Gliopathology is disease and region specific and produces multiple glial phenotypes that may be neuroprotective or neurotoxic. In this review we summarise recent knowledge on the role of glial purinergic signalling in cognitive-related neurological diseases.
This article is part of the Special Issue entitled ‘Purines in Neurodegeneration and Neuroregeneration’.
Modulation of the neuronal network activity by P2X receptors and their involvement in neurological disorders
2015, Pharmacological Research
ATP is a key energetic molecule, fundamental to cell function, which also has an important role in the extracellular milieu as a signaling molecule, acting as a chemoattractant for immune cells and as a neuro- and gliotransmitter. The ionotropic P2X receptors are members of an ATP-gated ion channels family. These ionotropic receptors are widely expressed through the body, with 7 subunits described in mammals, which are arranged in a trimeric configuration with a central pore permeable mainly to Ca²⁺ and Na⁺. All 7 subunits are expressed in different brain areas, being present in neurons and glia. ATP, through these ionotropic receptors, can act as a neuromodulator, facilitating the Ca²⁺-dependent release of neurotransmitters, inducing the cross-inhibition between P2XR and GABA receptors, and exercising by this way a modulation of synaptic plasticity. Growing evidence shows that P2XR play an important role in neuronal disorders and neurodegenerative diseases, like Parkinson's and Alzheimer's disease; this role involves changes on P2XR expression levels, activation of key pathways like GSK3β, APP processing, oxidative stress and inflammatory response. This review is focused on the neuromodulatory function of P2XR on pathophysiological conditions of the brain; the recent evidence could open a window to a new therapeutic target.

View all citing articles on Scopus

View full text

ReviewIonotropic ATP receptors in neuronal–glial communication

Abstract

Section snippets

Introduction: ATP mediated neurotransmission

Quantal ATP release from neuronal terminals and astroglia

P2X receptors in the CNS

Cortical astrocytes express P2X1/5 receptors with unique ATP sensitivity

Astroglial P2X7 receptors

Possible routes for P2X receptors-mediated bi-directional neuronal–glial signalling

The role for astroglial P2X receptors: reporters of physiological/pathological activity?

Acknowledgement

Plant Sci

Trends Neurosci

Mol Cell Neurosci

Neuroscience

Trends Neurosci

Trends Pharmacol Sci

Neuroscience

Neuron

J Biol Chem

J Biol Chem

Trends Pharmacol Sci

Neurosci Lett

Neuroscience

Prog Neurobiol

Cell Calcium

Biochem Biophys Res Commun

J Biol Chem

Neuropharmacology

Neuropharmacology

Neuropharmacology

Neuron

The birth and postnatal development of purinergic signalling

Acta Physiol (Oxf)

Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death

Cell Death Dis

Molecular physiology of P2X receptors

Physiol Rev

Signaling at purinergic P2X receptors

Annu Rev Physiol

Purinoceptors on neuroglia

Mol Neurobiol

International Union of Pharmacology. LVIII: Update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy

Pharmacol Rev

International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors

Pharmacol Rev

Adenosine signaling and function in glial cells

Cell Death Differ

ATP receptor-mediated synaptic currents in the central nervous system

Nature

Synaptic corelease of ATP and GABA in cultured spinal neurons

Nat Neurosci

A purinergic component of the excitatory postsynaptic current mediated by P2X receptors in the CA1 neurons of the rat hippocampus

Eur J Neurosci

Ionotropic P2X purinoreceptors mediate synaptic transmission in rat pyramidal neurones of layer II/III of somato-sensory cortex

J Physiol

ATP mediates excitatory synaptic transmission in mammalian neurones

Br J Pharmacol

Ionotropic receptors in neuronal–astroglial signalling: what is the role of “excitable” molecules in non-excitable cells

Biochim Biophys Acta

ATP receptors in pain sensation: involvement of spinal microglia and P2X4 receptors

Purinergic Signal

Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca2+ signaling

Science

Loss of IP3 receptor-dependent Ca2+ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity

J Neurosci

Mechanisms of transmitter release from astrocytes

Regulated ATP release from astrocytes through lysosome exocytosis

Nat Cell Biol

Connexin and pannexin mediated cell–cell communication

Neuron Glia Biol

Oxygen-glucose deprivation induces ATP release via maxi-anion channels in astrocytes

Purinergic Signal

Nonsynaptic communication through ATP release from volume-activated anion channels in axons

Sci Signal

Ischemia opens neuronal gap junction hemichannels

Science

The role of pannexin 1 hemichannels in ATP release and cell–cell communication in mouse taste buds

Proc Natl Acad Sci USA

Identification of a vesicular nucleotide transporter

Review
Ionotropic ATP receptors in neuronal–glial communication

Cortical astrocytes express P2X_1/5 receptors with unique ATP sensitivity

Astroglial P2X₇ receptors

ATP receptors in pain sensation: involvement of spinal microglia and P2X₄ receptors

Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca²⁺ signaling

Loss of IP₃ receptor-dependent Ca²⁺ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity