Increase in intracellular Ca2+ and calcitonin gene-related peptide release through metabotropic P2Y receptors in rat dorsal root ganglion neurons

Sanada, Mitsuru; Yasuda, Hitoshi; Omatsu‐Kanbe, Mariko; Sango, Kazunori; Isono, Takahiro; Matsuura, Hiroshi; Kikkawa, Ryuichi

doi:10.1016/s0306-4522(02)00005-2

Cited by 80 publications

(72 citation statements)

References 45 publications

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“…Their role in nociception is still under debate with both potential analgesic and algogenic actions. 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).…”

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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“…Autocrine͞paracrine action of released nucleotides thus may modulate neurotrophinpromoted neuronal differentiation during development. Expression of mRNA for multiple P2Y receptors, including P2Y 2 , has been detected in DRG neurons (29); in situ hybridization demonstrates P2Y 2 mRNA in 77% of such neurons in vivo (19). Furthermore, P2Y receptor transcripts are ubiquitously found in human central and peripheral nervous tissue samples (48); P2Y and certain P2X receptors are likely to be important physiologically as well as in neurological injury and disease (49).…”

Section: Discussionmentioning

confidence: 99%

“…DRG neurons express both TrkA (28) and P2 receptors (29), and neurite formation in DRG neurons is regulated by TrkA (30). Because neonatal DRG neurons undergo apoptosis in the absence of NGF, neurite growth experiments were conducted in the presence of the neurotrophin (31).…”

Section: Genetic or Sirna Depletion Of P2y2 Receptors Eliminates Atp␥mentioning

confidence: 99%

P2Y ₂ receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation

Arthur

Akassoglou²,

Insel³

2005

Proc. Natl. Acad. Sci. U.S.A.

109

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Neurotrophins are essential for neuronal differentiation, but the onset and the intensity of neurotrophin signaling within the neuronal microenvironment are poorly understood. We tested the hypothesis that extracellular nucleotides and their cognate receptors regulate neurotrophin-mediated differentiation. We found that 5 -O-(3-thio)triphosphate (ATP␥S) activation of the G protein-coupled receptor P2Y2 in the presence of nerve growth factor leads to the colocalization and association of tyrosine receptor kinase A and P2Y2 receptors and is required for enhanced neuronal differentiation. Consistent with these effects, ATP␥S promotes phosphorylation of tyrosine receptor kinase A, early response kinase 1͞2, and p38, thereby enhancing sensitivity to nerve growth factor and accelerating neurite formation in both PC12 cells and dorsal root ganglion neurons. Genetic or small interfering RNA depletion of P2Y2 receptors abolished the ATP␥S-mediated increase in neuronal differentiation. Moreover, in vivo injection of ATP␥S into the sciatic nerve increased growth-associated protein-43 (GAP-43), a marker for axonal growth, in wild-type but not P2Y2 ؊/؊ mice. The interactions of tyrosine kinase-and P2Y 2-signaling pathways provide a paradigm for the regulation of neuronal differentiation and suggest a role for P2Y 2 as a morphogen receptor that potentiates neurotrophin signaling in neuronal development and regeneration.neurotrophin signaling ͉ P2Y2 ͉ tyrosine receptor kinase A N eurite formation, a process extending from the cell soma and led by a growth cone, is a primary morphological event in neuronal differentiation, ultimately facilitating synaptic connections by neurons (1). Neuronal regeneration depends on the formation of neurites to repair injured or lost connections. These neuronal growth events require appropriate spatial and temporal expression and action of both initiation signals and promoter molecules (2). Neurotrophins, such as nerve growth factor (NGF), are key regulators of neuronal differentiation. NGF is released by target tissues, initiates neurite generation, maintains neuronal survival, prevents apoptosis, and promotes synapse formation (3-5). NGF signaling via the tyrosine receptor kinase A (TrkA) leads to stimulation of early response kinase 1͞2 (ERK1͞2) via Ras͞Raf pathways, which is required for differentiation, as well as the activation of the survival kinase, Akt (6). The regulation of NGF͞ TrkA signaling is determined by availability of NGF, as well as TrkA activation, characterized by receptor autophosphorylation, internalization, and retrograde transport from axons to cell bodies (7). Recent evidence has shown that receptor crosstalk is an important mechanism for regulation of neurotrophin signaling (6). The NGF͞ TrkA-signaling pathway converges with pain-related ion channels to regulate NGF-mediated heat sensitivity of sensory neurons (5) and with adenosine A 2A receptors to regulate neuronal survival (8). The contributions of other signal transduction pathways integrated with NGF͞TrkA signali...

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“…In contrast, we found that Src appears to play an important regulatory role in the signal transduction pathway that mediates this inhibition. PP2, an inhibitor of Src phosphorylation (Nagao et al, 1998), reversed the ATP␥S/P2Y 2 -mediated inhibition of DNA fragmentation in both PC12 cells and dorsal root ganglion (DRG) neurons, a peripheral nerve cell known to express P2Y 2 receptors (Sanada et al, 2002;Arthur et al, 2005) (Fig. 4 A).…”

Section: Erk and Akt Activation By P2y 2 Requires Srcmentioning

confidence: 99%

Inhibition of Apoptosis by P2Y₂Receptor Activation: Novel Pathways for Neuronal Survival

Arthur

Georgi²,

Akassoglou³

et al. 2006

J. Neurosci.

102

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Cell survival is an essential function in the development and maintenance of the nervous system. We demonstrate here a previously unappreciated role for extracellular nucleotide signaling through the P2Y 2 receptor in the survival of neurons: PC12 (pheochromocytoma 12) cells and dorsal root ganglion neurons are protected from serum starvation-induced apoptosis by ATP, UTP, and ATP␥S, an effect mediated via P2Y 2 receptors, as demonstrated by small interfering RNA and genetic knock-out models. This protection occurs independently of neurophin signaling but requires Src activation of ERK (extracellular signal-regulated kinase) and Akt. Moreover, ATP␥S and NGF act synergistically to enhance neuronal survival through enhanced TrkA signaling. The results, which define a novel mechanism for inhibition of apoptosis, implicate parallel, interacting systems-extracellular nucleotides/P2Y 2 receptors and neurotrophin/TrkA-to sustain neuronal survival.

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Increase in intracellular Ca2+ and calcitonin gene-related peptide release through metabotropic P2Y receptors in rat dorsal root ganglion neurons

Cited by 80 publications

References 45 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 ₂ receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation

Inhibition of Apoptosis by P2Y₂Receptor Activation: Novel Pathways for Neuronal Survival

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Increase in intracellular Ca2+ and calcitonin gene-related peptide release through metabotropic P2Y receptors in rat dorsal root ganglion neurons

Cited by 80 publications

References 45 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 2 receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation

Inhibition of Apoptosis by P2Y2Receptor Activation: Novel Pathways for Neuronal Survival

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

P2Y ₂ receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation

Inhibition of Apoptosis by P2Y₂Receptor Activation: Novel Pathways for Neuronal Survival