Metabotropic P2Y1 receptors inhibit P2X3 receptor-channels in rat dorsal root ganglion neurons

Gerevich, Zoltán; Müller, Christoph E.; Illéš, Peter

doi:10.1016/j.ejphar.2005.08.001

Cited by 56 publications

(48 citation statements)

References 23 publications

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“…For instance, although the activation of the uridine P2Y 2 receptor promotes CGRP release (Sanada et al, 2002), and facilitates capsaicininduced currents in rat dorsal root ganglia (DRG) (Gerevich and Illes, 2004), UTP and UDP were found to be analgesic when intrathecally injected to rats (Okada et al, 2002). Moreover, neuronal P2Y 1 receptors can downregulate P2X 3 receptor function in rat DRG (Gerevich et al, 2005), and its cognate ligand ADP can exert an antinociceptive role (Gerevich and Illes, 2004). Conversely, the selective inhibition of the ADP-sensitive P2Y 12 receptor subtype in vivo significantly suppresses neuropathic pain following spinal nerve ligation (Tsuda et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Ca_v2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain

Ceruti¹,

Villa²,

Fumagalli³

et al. 2011

J. Neurosci.

114

131

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Within the trigeminal ganglion, crosstalk between neurons and satellite glial cells (SGCs) contributes to neuronal sensitization and transduction of painful stimuli, including migraine pain, at least partly through activation of purinergic receptor mechanisms. We previously showed that the algogenic mediator bradykinin (BK) potentiates purinergic P2Y receptors on SGCs in primary trigeminal cultures. Our present study investigated the molecular basis of this effect in wild-type (WT) mice and Ca V 2.1 ␣1 R192Q mutant knock-in (KI) mice expressing a human mutation causing familial hemiplegic migraine type 1. Single-cell calcium imaging of WT cultures revealed functional BK receptors in neurons only, suggesting a paracrine action by BK to release a soluble mediator responsible for its effects on SGCs. We identified this mediator as the neuropeptide calcitonin gene-related peptide (CGRP), whose levels were markedly increased by BK, while the CGRP antagonist CGRP 8-37 and the anti-migraine drug sumatriptan inhibited BK actions. Unlike CGRP, BK was ineffective in neuron-free SGC cultures, confirming the CGRP neuronal source. P2Y receptor potentiation induced by CGRP in SGCs was mediated via activation of the extracellular signal-regulated kinase 1/2 pathways, and after exposure to CGRP, a significant release of several cytokines was detected. Interestingly, both basal and BK-stimulated CGRP release was higher in KI mouse cultures, where BK significantly upregulated the number of SGCs showing functional UTP-sensitive P2Y receptors. Our findings suggest that P2Y receptors on glial cells might be considered as novel players in the cellular processes underlying migraine pathophysiology and might represent new targets for the development of innovative therapeutic agents against migraine pain.

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Section: Discussionmentioning

confidence: 99%

Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Ca_v2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain

Ceruti¹,

Villa²,

Fumagalli³

et al. 2011

J. Neurosci.

114

131

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“…P2Y receptor expression in sensory nerve terminals could control ATP actions on algogenic P2X subtypes, as well. In fact, P2Y 1 and P2X3 receptors are often coexpressed in the same DRG neurons [30], and functional studies have shown that P2Y 1 receptor activation leads to P2X3 receptor inhibition [39].…”

Section: Modulation Of Pain Transmission By P2y Receptors In Sensory mentioning

confidence: 99%

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

Magni

Ceruti

2013

Biochemical Pharmacology

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Non-standard abbreviations:AR-C126313, 5-(7-chloro-4H-1-thia-3-aza-benzo[f]-4-yl)-3-methyl-6-thioxo-piperadin-2-one; AR-C67085, [[[[(2R,3S,4R,5R)-5-(6-amino-2-propylsulfanylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]-dichloromethyl]phosphonic acid; AR-C69931MX, [dichloro-[[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl) 3-[7-[[2-(3,4-BDNF, brain-derived neurotrophic factor; BK, bradykinin; CFA, Complete Freund's adjuvant; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglia; FHM1, familial hemiplegic migraine type 1; INS37217, P(1)-(uridine 5')-P(4)-(2'-deoxycytidine 5')tetraphosphate, tetrasodium salt; INS48823, {[(3aR,4R,6R,6aR)-2-benzyl-6-(2,4-dioxo-

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“…The animals were killed under CO 2 and decapitated to obtain cell cultures of DRG neurons. The isolation and culturing procedures of thoracic and lumbar DRG cells have been described in detail previously (28,29). DRG cells were plated at a density of 3 ϫ 10 4 cells onto 35-mm plastic dishes coated by poly-L-lysine (25 g/ml) (Sarstedt).…”

Section: Methodsmentioning

confidence: 99%

Dual Effect of Acid pH on Purinergic P2X3 Receptors Depends on the Histidine 206 Residue

Gerevich

Zádori

Köles

et al. 2007

Journal of Biological Chemistry

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Whole cell patch clamp investigations were carried out to clarify the pH sensitivity of native and recombinant P2X 3 receptors. In HEK293 cells permanently transfected with human (h) P2X 3 receptors (HEK293-hP2X 3 cells), an acidic pH shifted the concentration-response curve for ␣,␤-methylene ATP (␣,␤-meATP) to the right and increased its maximum. An alkalic pH did not alter the effect of ␣,␤-meATP. Further, a low pH value increased the activation time constant ( on ) of the ␣,␤-meATP current; the fast and slow time constants of desensitization ( des1 , des2 ) were at the same time also increased. Finally, acidification accelerated the recovery of P2X 3 receptors from the desensitized state. Replacement of histidine 206, but not histidine 45, by alanine abolished the pH-induced effects on hP2X 3 receptors transiently expressed in HEK293 cells. Changes in the intracellular pH had no effect on the amplitude or time course of the ␣,␤-meATP currents. The voltage sensitivity and reversal potential of the currents activated by ␣,␤-meATP were unaffected by extracellular acidification. Similar effects were observed in a subpopulation of rat dorsal root ganglion neurons expressing homomeric P2X 3 receptor channels. It is suggested that acidification may have a dual effect on P2X 3 channels, by decreasing the current amplitude at low agonist concentrations (because of a decrease in the rate of activation) and increasing it at high concentrations (because of a decrease in the rate of desensitization). Thereby, a differential regulation of pain sensation during e.g. inflammation may occur at the C fiber terminals of small DRG neurons in peripheral tissues.High proton concentrations have been registered in inflamed tissue (down to pH 5.4), after surgical interventions (down to pH 5.5), in fracture-related hematomas (down to pH 4.7), in cardiac ischemia (down to pH 5.7), and in and around malignant tumors (1-5). Therefore, local acidosis is considered to contribute to pain experienced in these states (5-11). It is also known that continuous administration of low pH buffered solutions into human skin evokes instant pain and hyperalgesia to mechanical stimulation (12). Electrophysiological experiments in rat skin nerve preparations showed that pathophysiologically relevant high proton concentrations produce a selective nonadapting excitation of nociceptors and a significant sensitization to mechanical stimulation (13). Thus, it has been proposed that local acidosis may play a major role in pain and hyperalgesia (7).Hydrogen ions are able to excite dorsal root ganglion (DRG) 2 neurons via the activation and/or modulation of inward cationselective currents, including the acid-sensing ion channels (ASICs) (14), the transient receptor potential vanilloid receptor 1 (TRPV1) (15, 16), and P2X receptors (17, 18). P2X receptors represent a family of ligand-gated cationic channels that open in response to the binding of ATP, possess two transmembrane domains, intracellular N and C termini, a large extracellular loop, and assemble as hom...

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Metabotropic P2Y1 receptors inhibit P2X3 receptor-channels in rat dorsal root ganglion neurons

Cited by 56 publications

References 23 publications

Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Ca_v2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain

Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Ca_v2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

Dual Effect of Acid pH on Purinergic P2X3 Receptors Depends on the Histidine 206 Residue

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Metabotropic P2Y1 receptors inhibit P2X3 receptor-channels in rat dorsal root ganglion neurons

Cited by 56 publications

References 23 publications

Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Cav2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain

Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Cav2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

Dual Effect of Acid pH on Purinergic P2X3 Receptors Depends on the Histidine 206 Residue

Contact Info

Product

Resources

About

Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Ca_v2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain

Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Ca_v2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain