Spinal Adenosine A2a Receptor Activation Elicits Long-Lasting Phrenic Motor Facilitation

Golder, Francis J.; Ranganathan, Lavanya; Satriotomo, Irawan; Hoffman, Michael; Lovett-Barr, Mary Rachael; Watters, Jyoti J.; Baker-Herman, Tracy L.; Mitchell, Gordon S.

doi:10.1523/jneurosci.3570-07.2008

Cited by 143 publications

(178 citation statements)

References 40 publications

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“…In addition to these behavioural changes, we found a large reduction in the level of Conflicting results have been obtained from binding studies and autoradiography [3,7,8], and functional studies have reported some inconsistent effects of A 2A receptor ligands [1,5,15,16,25,28,36]. mRNA for the A 2A receptor has been reported to be expressed in the dorsal root ganglion but not in the spinal cord [20,21] suggesting that A 2A receptors could be present on the peripheral terminals of the sensory nerves but not to any significant extent in the spinal cord, as suggested by Sawynok [32].…”

Section: Introductionsupporting

confidence: 45%

Genetic deletion of the adenosine A2A receptor in mice reduces the changes in spinal cord NMDA receptor binding and glucose uptake caused by a nociceptive stimulus

Hussey

Clarke

Ledent

et al. 2010

Neuroscience Letters

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Section: Introductionsupporting

confidence: 45%

Genetic deletion of the adenosine A2A receptor in mice reduces the changes in spinal cord NMDA receptor binding and glucose uptake caused by a nociceptive stimulus

Hussey

Clarke

Ledent

et al. 2010

Neuroscience Letters

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“…Here we demonstrate that EPAC-dependent, 5-HT 7 receptor-induced pMF is mechanistically distinct from the serotonin-induced PKA-ERK-brainderived neurotrophic factor (BDNF) signaling pathway described in invertebrate model systems (for review see Kandel 2012). As shown by the available evidence concerning 5-HT 7 receptor-induced pMF, 5-HT 7 receptors elicit pMF via EPACAkt-mTORC1 signaling, resulting in new synthesis of an immature TrkB isoform (Golder et al 2008;Hoffman and Mitchell 2011). This mechanism is independent of PKA, ERK signaling, or new BDNF synthesis (Hoffman and Mitchell 2011).…”

Section: Discussionmentioning

confidence: 75%

Spinal 5-HT₇ receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling

Fields

Springborn

Mitchell

2015

Journal of Neurophysiology

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Fields DP, Springborn SR, Mitchell GS. Spinal 5-HT 7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling. J Neurophysiol 114: -2022. First published August 12, 2015 doi:10.1152/jn.00374.2015.-Spinal serotonin type 7 (5-HT 7 ) receptors elicit complex effects on motor activity. Whereas 5-HT 7 receptor activation gives rise to long-lasting phrenic motor facilitation (pMF), it also constrains 5-HT 2 receptor-induced pMF via "cross-talk inhibition." We hypothesized that divergent cAMP-dependent signaling pathways give rise to these distinct 5-HT 7 receptor actions. Specifically, we hypothesized that protein kinase A (PKA) mediates cross-talk inhibition of 5-HT 2 receptor-induced pMF whereas 5-HT 7 receptor-induced pMF results from exchange protein activated by cAMP (EPAC) signaling. Anesthetized, paralyzed, and ventilated rats receiving intrathecal (C 4 ) 5-HT 7 receptor agonist (AS-19) injections expressed pMF for Ͼ90 min, an effect abolished by pretreatment with a selective EPAC inhibitor (ESI-05) but not a selective PKA inhibitor (KT-5720). Furthermore, intrathecal injections of a selective EPAC activator (8-pCPT-2=-Me-cAMP) were sufficient to elicit pMF. Finally, spinal mammalian target of rapamycin complex-1 (mTORC1) inhibition via intrathecal rapamycin abolished 5-HT 7 receptor-and EPAC-induced pMF, demonstrating that spinal 5-HT 7 receptors elicit pMF by an EPAC-mTORC1 signaling pathway. Thus 5-HT 7 receptors elicit and constrain spinal phrenic motor plasticity via distinct signaling mechanisms that diverge at cAMP (EPAC vs. PKA). Selective manipulation of these molecules may enable refined regulation of serotonin-dependent spinal motor plasticity for therapeutic advantage. motor neuron; phrenic nerve; spinal cord; respiratory plasticity; neuroplasticity; 5-HT 7 ; receptor; exchange protein activated by cAMP; protein kinase A; rapamycin; mTOR SEROTONIN PLAYS A KEY ROLE in important forms of sensorymotor plasticity, including sensitization of the gill withdrawal reflex in Aplysia (reviewed in Kandel 2012). For example, episodic serotonin presentations enhance sensory motor synaptic transmission, giving rise to the gill withdrawal reflex (Brunelli et al. 1976). This well-studied form of plasticity in an invertebrate model system relies on multiple serotonin receptor subtypes, each activating unique kinase signaling cascades (Barbas et al. 2003).In ways similar to sensory motor facilitation in Aplysia, episodic serotonin receptor activation is necessary and sufficient for important forms of spinal respiratory motor plasticity, such as long-lasting (Ͼ90 min) phrenic motor facilitation (pMF) following acute intermittent hypoxia (AIH; reviewed by Mahamed and Mitchell 2007;Dale-Nagle et al. 2010;Devinney et al. 2013) or direct injections of serotonin or serotonin receptor agonists into the cervical spinal cord of rats (Hoffman

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“…13 In fact, at this early time post-injury, we suggest that A2A receptor inhibition may limit the potential for alternative, adenosine-dependent pathways to respiratory motor plasticity. 7,25 With this idea in mind, it is possible that the plasticity promoting actions of combinatorial actions of intermittent hypoxia and A2A receptor inhibition in normal or chronic SCI rats may actually undermine intermittent hypoxia-induced plasticity in rats with acute SCI. Something as simple as drinking coffee (a well-known A2A receptor antagonist) may have major, but different consequences with time post-spinal injury.…”

Section: A2a Inhibition Enhances Long-term Facilitationmentioning

confidence: 99%

Adenosine 2A Receptor Inhibition Enhances Intermittent Hypoxia-Induced Diaphragm but Not Intercostal Long-Term Facilitation

Navarrete‐Opazo

Vinit²,

Mitchell³

2014

Journal of Neurotrauma

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Acute intermittent hypoxia (AIH) elicits diaphragm (Dia) and second external intercostal (T2 EIC) long-term facilitation (LTF) in normal unanesthetized rats. Although AIH-induced phrenic LTF is serotonin dependent, adenosine constrained in anesthetized rats, this has not been tested in unanesthetized animals. Cervical (C2) spinal hemisection (C2HS) abolishes phrenic LTF because of loss of serotonergic inputs 2 weeks post-injury, but LTF returns 8 weeks post-injury. We tested three hypotheses in unanesthetized rats: (1) systemic adenosine 2aA (A2A) receptor inhibition with intraperitoneal (IP) KW6002 enhances Dia and T2 EIC LTF in normal rats; (2) Dia and T2 EIC LTF are expressed after chronic (8 weeks), but not acute (1 week) C2HS; and (3) KW6002 enhances Dia and T2 EIC LTF after chronic (not acute) C2HS. Electromyography radiotelemetry was used to record Dia and T2 EIC activity during normoxia (21% O 2 ), before and after AIH (10, 5-min 10.5% O 2 , 5-min intervals). In normal rats, KW6002 enhanced DiaLTF versus AIH alone (33.1 -4.6% vs. 22.1 -6.4% baseline, respectively; p < 0.001), but had no effect on T2 EIC LTF ( p > 0.05). Although Dia and T2 EIC LTF were not observed 2 weeks post-C2HS, LTF was observed in contralateral (uninjured) Dia and T2 EIC 8 weeks post-C2HS (18.7 -2.7% and 34.9 -4.9% baseline, respectively; p < 0.05), with variable ipsilateral expression. KW6002 had no significant effects on contralateral Dia ( p = 0.447) or T2 EIC LTF ( p = 0.796). We conclude that moderate AIH induces Dia and T2 EIC LTF after chronic, but not acute cervical spinal injuries. A single A2A receptor antagonist dose enhances AIH-induced Dia LTF in normal rats, but this effect is not significant in chronic (8 weeks) C2HS unanesthetized rats.

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Spinal Adenosine A2a Receptor Activation Elicits Long-Lasting Phrenic Motor Facilitation

Cited by 143 publications

References 40 publications

Genetic deletion of the adenosine A2A receptor in mice reduces the changes in spinal cord NMDA receptor binding and glucose uptake caused by a nociceptive stimulus

Genetic deletion of the adenosine A2A receptor in mice reduces the changes in spinal cord NMDA receptor binding and glucose uptake caused by a nociceptive stimulus

Spinal 5-HT₇ receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling

Adenosine 2A Receptor Inhibition Enhances Intermittent Hypoxia-Induced Diaphragm but Not Intercostal Long-Term Facilitation

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Spinal Adenosine A2a Receptor Activation Elicits Long-Lasting Phrenic Motor Facilitation

Cited by 143 publications

References 40 publications

Genetic deletion of the adenosine A2A receptor in mice reduces the changes in spinal cord NMDA receptor binding and glucose uptake caused by a nociceptive stimulus

Genetic deletion of the adenosine A2A receptor in mice reduces the changes in spinal cord NMDA receptor binding and glucose uptake caused by a nociceptive stimulus

Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling

Adenosine 2A Receptor Inhibition Enhances Intermittent Hypoxia-Induced Diaphragm but Not Intercostal Long-Term Facilitation

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Spinal 5-HT₇ receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling