An intracellular motif of P2X<sub>3</sub> receptors is required for functional cross‐talk with GABA<sub>A</sub> receptors in nociceptive DRG neurons

Toulmé, Estelle; Blais, Dominique; Léger, Claire; Landry, Marc; Garret, Maurice; Séguéla, Philippe; Boué‐Grabot, Éric

doi:10.1111/j.1471-4159.2007.04640.x

Cited by 42 publications

(35 citation statements)

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“…In our current work, cross-inhibition between recombinant P2X4 and GABA A receptors was voltage-and ion-independent, which is consistent with the previous studies of other P2X subtypes and cys loop receptor members (12)(13)(14)(15)(16)(17)(18)(19)21). In addition, our biochemical and immunohistochemical experiments in transfected cells and SF-1 GFP-positive neurons further provide the cellular mechanisms that mediate cross-inhibition between the two distinct receptors.…”

Section: Discussionsupporting

confidence: 91%

“…Finally, we provide evidence that two residues (Tyr 374 , Val 375 ) in the C terminus of P2X4 receptor are required for the physical interaction between P2X4 and GABA A receptors. This motif is absent from other P2X subtypes, including GABA A receptor-interacting P2X2 or P2X3 subunits (18,21), suggesting that P2X subunit-specific molecular determinants are involved in functional interactions with other ligand-gated channels. Among P2X receptors, P2X4-containing receptors constitutively cycle into and out of the membrane by a dynamin-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…ATP is released either with an inhibitory neurotransmitter, GABA 4 (7)(8)(9)(10) or with an excitatory neurotransmitter, glutamate in the CNS (4,11). Recent studies have clearly demonstrated the interactions of P2X receptors with other ligand-gated channels, including 5-hydroxytryptamine, GABA A , or nicotinic receptors in recombinant expression and cell culture preparations (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). It thus appears that P2X receptors prefer to interact with other receptors rather than act independently.…”

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Cross-talk between P2X4 and γ-Aminobutyric Acid, Type A Receptors Determines Synaptic Efficacy at a Central Synapse

Donier

Martínez

et al. 2011

Journal of Biological Chemistry

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The essence of neuronal function is to generate outputs in response to synaptic potentials. Synaptic integration at postsynaptic sites determines neuronal outputs in the CNS. Using immunohistochemical and electrophysiological approaches, we first reveal that steroidogenic factor 1 (SF-1) green fluorescent protein (GFP)-positive neurons in the ventromedial nucleus of the hypothalamus express P2X4 subunits that are activated by exogenous ATP. Increased membrane expression of P2X4 channels by using a peptide competing with P2X4 intracellular endocytosis motif enhances neuronal excitability of SF-1 GFP-positive neurons. This increased excitability is inhibited by a P2X receptor antagonist. Furthermore, increased surface P2X4 receptor expression significantly decreases the frequency and the amplitude of GABAergic postsynaptic currents of SF-1 GFPpositive neurons. Co-immunopurification and pulldown assays reveal that P2X4 receptors complex with aminobutyric acid, type A (GABA A ) receptors and demonstrate that two amino acids in the carboxyl tail of the P2X4 subunit are crucial for its physical association with GABA A receptors. Mutation of these two residues prevents the physical association, thereby blocking cross-inhibition between P2X4 and GABA A receptors. Moreover, disruption of the physical coupling using competitive peptides containing the identified motif abolishes current inhibition between P2X4 and GABA A receptors in recombinant system and P2X4 receptor-mediated GABAergic depression in SF-1 GFP-positive neurons. Our present work thus provides evidence for cross-talk between excitatory and inhibitory receptors that appears to be crucial in determining GABAergic synaptic strength at a central synapse.ATP acts at cell surface receptors of two fundamentally distinct types: ligand-gated ion channels (P2X receptors) and G-protein-coupled receptors (P2Y receptors). ATP P2X receptors are widely distributed in excitable and non-excitable cells of vertebrates and are nonselective cation channels (1). Their activation mediates membrane depolarization and calcium influx (2). Among the seven P2X subunits, P2X4 receptors are most widely distributed in the CNS (3). It appears that P2X4-containing receptors are involved in purinergic synaptic transmission at central synapses since they are located at postsynaptic sites in the brain, including the hippocampus and the cerebellum (4). Although there is increasing evidence for their implications in various physiological and pathological conditions (5), the physiological role of P2X receptors at the synaptic level has been poorly defined, at least in part, due to the paucity of purinergic synaptic transmission in the CNS.In the nervous system, ATP appears to be primarily a cotransmitter rather than a principal transmitter (6). ATP is released either with an inhibitory neurotransmitter, GABA 4 (7-10) or with an excitatory neurotransmitter, glutamate in the CNS (4, 11). Recent studies have clearly demonstrated the interactions of P2X receptors with other ligand-gated channels, i...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cross-talk between P2X4 and γ-Aminobutyric Acid, Type A Receptors Determines Synaptic Efficacy at a Central Synapse

Donier

Martínez

et al. 2011

Journal of Biological Chemistry

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“…A prerequisite for such a mechanism is the close proximity of receptors. Previous work confirmed physical interactions for combinations of P2X2-a4b2, P2X2-5-HT 3 , and P2X2-GABA C receptors (Khakh et al, 2000(Khakh et al, , 2005Boué-Grabot et al, 2003, 2004aToulmé et al, 2007;Decker and Galligan, 2010;Jo et al, 2011;Shrivastava et al, 2011). The evidence for physical contact suggests that there is no major role for second messengers generated by endogenous and electrophysiologically silent metabotropic P2Y receptors in the cross inhibition.…”

Section: Introductionsupporting

confidence: 58%

Subtype-Specific Mechanisms for Functional Interaction between α6β4* Nicotinic Acetylcholine Receptors and P2X Receptors

2014

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P2X receptors and nicotinic acetylcholine receptors (nAChRs) display functional and physical interactions in many cell types and heterologous expression systems, but interactions between a6b4-containing (a6b4*) nAChRs and P2X2 receptors and/or P2X3 receptors have not been fully characterized. We measured several types of crosstalk in oocytes coexpressing a6b4 nAChRs and P2X2, P2X3, or P2X2/3 receptors. A novel form of crosstalk occurs between a6b4 nAChRs and P2X2 receptors. P2X2 receptors were forced into a prolonged desensitized state upon activation by ATP through a mechanism that does not depend on the intracellular C terminus of the P2X2 receptors. Coexpression of a6b4 nAChRs with P2X3 receptors shifts the ATP dose-response relation to the right, even in the absence of acetylcholine (ACh). Moreover, currents become nonadditive when ACh and ATP are coapplied, as previously reported for other Cys-loop receptors interacting with P2X receptors, and this crosstalk is dependent on the presence of the P2X3 C-terminal domain. P2X2 receptors also functionally interact with a6b4b3 but through a different mechanism from a6b4. The interaction with P2X3 receptors is less pronounced for the a6b4b3 nAChR than the a6b4 nAChR. We also measured a functional interaction between the a6b4 nAChRs and the heteromeric P2X2/3 receptor. Experiments with the nAChR channel blocker mecamylamine on P2X2-a6b4 oocytes point to the loss of P2X2 channel activity during the crosstalk, whereas the ion channel pores of the P2X receptors were fully functional and unaltered by the receptor interaction for P2X2-a6b4b3, P2X2/3-a6b4, and P2X2/3-a6b4b3. These results may be relevant to dorsal root ganglion cells and to other neurons that coexpress these receptor subunits.

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“…By evaluating inhibition of both channels simultaneously, this work also contributes to the growing appreciation of the interaction and cooperation between distinct ion channels, which is not uncommon [e.g., TRPV1-TRPA1 (42) and P2X3-GABA A (44)] and may prove important for guiding drug development. With regard to limitations, the single-fiber work focused exclusively on PN colorectal afferents to build on previous studies in this same afferent population (19,20,39).…”

Section: Discussionmentioning

confidence: 99%

Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization

Kiyatkin

Feng

Schwartz

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Kiyatkin ME, Feng B, Schwartz ES, Gebhart GF. Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization. Am J Physiol Gastrointest Liver Physiol 305: G638 -G648, 2013. First published August 29, 2013; doi:10.1152/ajpgi.00180.2013.-The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity. pelvic nerve; purinergic receptor; single fiber; transient receptor potential; visceral pain CHRONIC ABDOMINAL PAIN is a key feature of irritable bowel syndrome (IBS), which is prevalent, costly, and difficult to manage. An important contributor to pain in IBS is heightened perception of mechanical events in the bowel (i.e., hypersensitivity). Indeed, patients with IBS typically report greater pain and/or reduced response thresholds to rectal balloon distension than control subjects (3,24,28,34,46). Although central processes contribute to colorectal hypersensitivity, the driving force is increased afferent mechanosensitivity (i.e., sensitization). For example, intrarectal lidocaine reduces pain evoked by rectal distension in healthy subjects as well as ongoing pain and both vi...

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An intracellular motif of P2X₃ receptors is required for functional cross‐talk with GABA_A receptors in nociceptive DRG neurons

Cited by 42 publications

References 40 publications

Cross-talk between P2X4 and γ-Aminobutyric Acid, Type A Receptors Determines Synaptic Efficacy at a Central Synapse

Cross-talk between P2X4 and γ-Aminobutyric Acid, Type A Receptors Determines Synaptic Efficacy at a Central Synapse

Subtype-Specific Mechanisms for Functional Interaction between α6β4* Nicotinic Acetylcholine Receptors and P2X Receptors

Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization

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An intracellular motif of P2X3 receptors is required for functional cross‐talk with GABAA receptors in nociceptive DRG neurons

Cited by 42 publications

References 40 publications

Cross-talk between P2X4 and γ-Aminobutyric Acid, Type A Receptors Determines Synaptic Efficacy at a Central Synapse

Cross-talk between P2X4 and γ-Aminobutyric Acid, Type A Receptors Determines Synaptic Efficacy at a Central Synapse

Subtype-Specific Mechanisms for Functional Interaction between α6β4* Nicotinic Acetylcholine Receptors and P2X Receptors

Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization

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An intracellular motif of P2X₃ receptors is required for functional cross‐talk with GABA_A receptors in nociceptive DRG neurons