Enhancement of the response in spinal dorsal horn neurons by cAMP-dependent protein kinase

Cerne, R.; Rusin, K.I.; Randić, Mirjana

doi:10.1016/0304-3940(93)90275-p

Cited by 107 publications

(48 citation statements)

References 20 publications

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“…Activation of several receptors for sensory transmitters such as glutamate and CGRP has been reported to raise cAMP levels. In slices or isolated cells from young animals, cAMP analogue enhanced glutamate receptor-mediated synaptic responses (Cerne et al 1992(Cerne et al , 1993 or no effect on AMPA/kainate receptor-mediated synaptic responses (Hori et al 1996). In the present studies, application of forskolin did not significantly affect synaptic responses induced by dorsal root stimulation in slices of adult mice.…”

Section: Synergistic Effect Between Camp and Serotonincontrasting

confidence: 51%

Synergistic Enhancement of Glutamate-Mediated Responses by Serotonin and Forskolin in Adult Mouse Spinal Dorsal Horn Neurons

Wang

Zhuo

2002

Journal of Neurophysiology

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Wang, Guo-Du and Min Zhuo. Synergistic enhancement of glutamate-mediated responses by serotonin and forskolin in adult mouse spinal dorsal horn neurons. J Neurophysiol 87: 732-739, 2002; 10.1152/jn.00423.2001. Glutamate is the major excitatory amino acid neurotransmitter in the CNS, including the neocortex, hippocampus, and spinal cord. Normal synaptic transmission is mainly mediated by glutamate AMPA and/or kainate receptors. Glutamate N-methyl-Daspartate (NMDA) receptors are normally inactive and only activated when a sufficient postsynaptic depolarization is induced by the activity. Here we show that in sensory synapses of adult mouse, some synaptic responses (26.3% of a total of 38 experiments) between primary afferent fibers and dorsal horn neurons are almost completely mediated by NMDA receptors. Dorsal root stimulation did not elicit any detectable AMPA/kainate receptor-mediated responses in these synapses. Unlike young spinal cord, serotonin alone did not produce any long-lasting synaptic enhancement in adult spinal dorsal horn neurons. However, co-application of the adenylyl cyclase activator forskolin and serotonin (5-HT) produced long-lasting enhancement, including the recruitment of functional AMPA receptor-mediated responses. Calcium-sensitive, calmodulin-regulated adenylyl cyclases (AC1, AC8) are required for the enhancement. Furthermore the thresholds for generating action potential responses were decreased, and, in many cases, co-application of forskolin and 5-HT led to the generation of action potentials by previously subthreshold stimulation of primary afferent fibers in the presence of the NMDA receptor blocker 2-amino-5-phosphonovaleric acid. Our results suggest that pure NMDA synapses exist on sensory neurons in adult spinal cord and that they may contribute to functional sensory transmission. The synergistic recruitment of functional AMPA responses by 5-HT and forskolin provides a new cellular mechanism for glutamatergic synapses in mammalian spinal cord.

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Section: Synergistic Effect Between Camp and Serotonincontrasting

confidence: 51%

Synergistic Enhancement of Glutamate-Mediated Responses by Serotonin and Forskolin in Adult Mouse Spinal Dorsal Horn Neurons

Wang

Zhuo

2002

Journal of Neurophysiology

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“…In vitro, PKA phosphorylates the NR1 subunit of the NMDA receptor (32,33). Forskolin enhances NMDA receptor activity in spinal cord dorsal horn neurons and in hippocampal neurons in culture (34,35), and the NMDA receptorassociated protein, Yotiao (36), interacts with PKA holoenzyme and type 1 protein phosphatase (37). Taken together, these findings strongly suggest that the cAMP machinery is compartmentalized within close proximity to RACK1 and the NMDA receptor, allowing the rapid dissociation of RACK1 upon activation of a G␣ s -coupled receptor, and the rapid regulation of the NMDA receptor function.…”

Section: Discussionmentioning

confidence: 99%

Pituitary Adenylate Cyclase-activating Polypeptide (PACAP(1–38)) Enhances N-Methyl-d-aspartate Receptor Function and Brain-derived Neurotrophic Factor Expression via RACK1

Yaka

Phamluong

et al. 2003

Journal of Biological Chemistry

160

189

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A. 99, 5710 -5715). Here, we identified the signaling cascade by which RACK1 is released from the NMDA receptor complex and identified the consequences of the dissociation. We found that activation of the cAMP/protein kinase A pathway in hippocampal slices induced the release of RACK1 from NR2B and Fyn. This resulted in the induction of NR2B phosphorylation and the enhancement of NMDA receptor-mediated activity via Fyn. We identified the neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP(1-38)), as a ligand that induced phosphorylation of NR2B and enhanced NMDA receptor potentials. Finally, we found that activation of the cAMP/protein kinase A pathway induced the movement of RACK1 to the nuclear compartment in dissociated hippocampal neurons. Nuclear RACK1 in turn was found to regulate the expression of brain-derived neurotrophic factor induced by PACAP(1-38). Taken together our results suggest that activation of adenylate cyclase by PACAP(1-38) results in the release of RACK1 from the NMDA receptor and Fyn. This in turn leads to NMDA receptor phosphorylation, enhanced activity mediated by Fyn, and to the induction of brain-derived neurotrophic factor expression by RACK1. The ionotropic glutamate receptor subtype, N-methyl-D-as-1 plays an essential role in neuronal development, excitotoxicity, synaptic plasticity, and learning and memory (2). The ligand-gated NMDA receptor channel is a heteromer comprised of NR1 and at least one of four NR2 subunits (A-D) (3). The cytoplasmic tail of the NR2B subunit is phosphorylated on tyrosine residues (4) and is the most abundant tyrosine-phosphorylated protein in the postsynaptic density (5). Phosphorylation of NMDA receptor subunits regulates the activity of the channel (6). Specifically, application of a tyrosine kinase inhibitor causes a progressive decrease in NMDA receptor-mediated currents, and conversely, inhibition of protein-tyrosine phosphatases results in an increase in NMDA receptor-mediated currents (7). Subsequent studies have identified the Src family of protein-tyrosine kinases (PTKs) as enzymes that phosphorylate the NR2 subunits, regulating NMDA receptor activities (6 -8). Hence, modulation of NMDA receptor phosphorylation by Src family protein-tyrosine kinases is likely to play an important role in modulating glutamate-mediated pathways. In the recent years it has become increasingly apparent that the formation of localized signaling complexes, which include receptors, kinases, phosphatases and their substrates, are highly important for the regulation of signal transduction cascades (9, 10). Scaffolding proteins play a major role in the assembly of such signaling complexes (11). Recently, we identified the scaffolding protein RACK1 as a novel regulator of the phosphorylation state and function of the NMDA receptor. We found that RACK1 interacts with both the cytoplasmic tail of the NR2B subunit and Fyn and inhibits the ability of Fyn to phosphorylate the NR2B subunit and consequently inhibits NMDA receptor-mediated excitatory postsyna...

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“…Phosphorylation of NR1 would be expected to enhance neuron excitability by increasing the number of NMDA receptors transported to the cell membrane and increasing glutamate-induced currents through NMDA receptors (9,17,49,65). The NMDA receptor in the RVM is critical for the development of hyperalgesia after muscle insult, with our prior studies showing blockade of NMDA receptors reduces hyperalgesia, increasing NR1 enhances nociception, and decreasing NR1 prevents chronic muscle hyperalgesia (13,53).…”

Section: Mechanisms Of Exercise-induced Analgesiamentioning

confidence: 99%

Regular physical activity prevents development of chronic pain and activation of central neurons

Sluka

O’Donnell

Danielson

et al. 2013

Journal of Applied Physiology

162

168

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Enhancement of the response in spinal dorsal horn neurons by cAMP-dependent protein kinase

Cited by 107 publications

References 20 publications

Synergistic Enhancement of Glutamate-Mediated Responses by Serotonin and Forskolin in Adult Mouse Spinal Dorsal Horn Neurons

Synergistic Enhancement of Glutamate-Mediated Responses by Serotonin and Forskolin in Adult Mouse Spinal Dorsal Horn Neurons

Pituitary Adenylate Cyclase-activating Polypeptide (PACAP(1–38)) Enhances N-Methyl-d-aspartate Receptor Function and Brain-derived Neurotrophic Factor Expression via RACK1

Regular physical activity prevents development of chronic pain and activation of central neurons

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