Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT1 receptor signaling

<p>Abstract</p> <p>Background</p> <p>The aberrant release of the neurotransmitters, glutamate and calcitonin-gene related peptide (CGRP), from trigeminal neurons has been implicated in migraine. The voltage-gated P/Q-type calcium channel has a critical role in controlling neurotransmitter release and has been linked to Familial Hemiplegic Migraine. Therefore, we examined the importance of voltage-dependent calcium channels in controlling release of glutamate and CGRP from trigeminal ganglion neurons isolated from male and female rats and grown in culture. Serotonergic pathways are likely involved in migraine, as triptans, a class of 5-HT₁receptor agonists, are effective in the treatment of migraine and their effectiveness may be due to inhibiting neurotransmitter release from trigeminal neurons. We also studied the effect of serotonin receptor activation on release of glutamate and CGRP from trigeminal neurons grown in culture.</p> <p>Results</p> <p>P/Q-, N- and L-type channels each mediate a significant fraction of potassium-stimulated release of glutamate and CGRP. We determined that 5-HT significantly inhibits potassium-stimulated release of both glutamate and CGRP. Serotonergic inhibition of both CGRP and glutamate release can be blocked by pertussis toxin and NAS-181, a 5-HT_1B/1Dantagonist. Stimulated release of CGRP is unaffected by Y-25130, a 5-HT₃antagonist and SB 200646, a 5-HT_2B/2Cantagonist.</p> <p>Conclusion</p> <p>These data suggest that release of both glutamate and CGRP from trigeminal neurons is controlled by calcium channels and modulated by 5-HT signaling in a pertussis-toxin dependent manner and probably via 5-HT₁receptor signaling. This is the first characterization of glutamate release from trigeminal neurons grown in culture.</p

Insulin signaling inhibits the 5-HT(2C )receptor in choroid plexus via MAP kinase

BACKGROUND: G protein-coupled receptors (GPCRs) interact with heterotrimeric GTP-binding proteins (G proteins) to modulate acute changes in intracellular messenger levels and ion channel activity. In contrast, long-term changes in cellular growth, proliferation and differentiation are often mediated by tyrosine kinase receptors and certain GPCRs by activation of mitogen-activated protein (MAP) kinases. Complex interactions occur between these signaling pathways, but the specific mechanisms of such regulatory events are not well-understood. In particular it is not clear whether GPCRs are modulated by tyrosine kinase receptor-MAP kinase pathways. RESULTS: Here we describe tyrosine kinase receptor regulation of a GPCR via MAP kinase. Insulin reduced the activity of the 5-HT(2C )receptor in choroid plexus cells which was blocked by the MAP kinase kinase (MEK) inhibitor, PD 098059. We demonstrate that the inhibitory effect of insulin and insulin-like growth factor type 1 (IGF-1) on the 5-HT(2C )receptor is dependent on tyrosine kinase, RAS and MAP kinase. The effect may be receptor-specific: insulin had no effect on another GPCR that shares the same G protein signaling pathway as the 5-HT(2C )receptor. This effect is also direct: activated MAP kinase mimicked the effect of insulin, and removing a putative MAP kinase site from the 5-HT(2C )receptor abolished the effect of insulin. CONCLUSION: These results show that insulin signaling can inhibit 5-HT(2C )receptor activity and suggest that MAP kinase may play a direct role in regulating the function of a specific GPCR

Team reasoning and the rational choice of payoff-dominant outcomes in games

Standard game theory cannot explain the selection of payoff-dominant outcomes that are best for all players in common-interest games. Theories of team reasoning can explain why such mutualistic cooperation is rational. They propose that teams can be agents and that individuals in teams can adopt a distinctive mode of reasoning that enables them to do their part in achieving Pareto-dominant outcomes. We show that it can be rational to play payoff-dominant outcomes, given that an agent group identifies. We compare team reasoning to other theories that have been proposed to explain how people can achieve payoff-dominant outcomes, especially with respect to rationality. Some authors have hoped that it would be possible to develop an argument that it is rational to group identify. We identify some large—probably insuperable—problems with this project and sketch some more promising approaches, whereby the normativity of group identification rests on morality

Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HTreceptor signaling-3

in the absence and presence of 50 mM KCl and/or drugs. Drugs were present as indicated during "Pretreat" and "50 mM KCl" incubations but not during the "Basal" incubation. Data is presented as the mean ± S.E.M. and the number of wells tested is indicated in parentheses. An asterisk indicates a significant difference (p < 0.05) between the transmitter release from control cells and from cells treated with calcium channel blockers. Potassium-stimulated release of glutamate was inhibited by 1 μM ω-Aga TK, 1 μM ω-Cgtx GVIA and 1 μM nimodipine while basal glutamate release was not altered (Panel A). Potassium-stimulated release of CGRP was inhibited by 1 μM ω-Aga TK, 1 μM ω-Cgtx GVIA and 1 μM nimodipine while basal CGRP release was not altered (Panel B).<p><b>Copyright information:</b></p><p>Taken from "Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HTreceptor signaling"</p><p>http://www.molecularpain.com/content/4/1/12</p><p>Molecular Pain 2008;4():12-12.</p><p>Published online 16 Apr 2008</p><p>PMCID:PMC2359740.</p><p></p

Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HTreceptor signaling-1

Ions in the absence and presence of 50 mM KCl and/or drugs. Drugs were present as indicated during "Pretreat" and "50 mM KCl" incubations but not during the "Basal" incubation. Data is presented as the mean ± S.E.M. and the number of wells tested is indicated in parentheses. An asterisk indicates a significant difference (p < 0.05) between the transmitter release from control cells and from cells treated with serotonin and/or pertussis toxin. Serotonin (10 μM) inhibits KCl-stimulated but not basal release of glutamate (Panel A). Overnight pertussis toxin treatment (100 ng/ml) blocks the serotonergic inhibition of KCl-stimulated glutamate release without affecting basal or KCl-stimulated release. Serotonin (10 μM) inhibits KCl-stimulated but not basal release of CGRP (Panel B). Overnight pertussis toxin treatment (100 ng/ml) blocks the serotonergic inhibition of KCl-stimulated CGRP release without affecting basal or KCl-stimulated release from trigeminal neurons. Serotonin inhibits KCl-stimulated release of CGRP from trigeminal neurons from female rats in the absence and presence of the calcium channel blockers, 1 μM ω-Cgtx GVIA and 1 μM nimodine to a similar extent (Panel C). Serotonin (1 μM) reversibly inhibits calcium current amplitude (Panel D). Peak currents were plotted against time for this cell. The trigeminal neurons were depolarized to 0 mV for 100 msec every 20 seconds from a holding potential of -80 mV. The horizontal bar indicates perfusion of 1 μM 5-HT. Inset, superimposed current traces from the indicated time points.<p><b>Copyright information:</b></p><p>Taken from "Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HTreceptor signaling"</p><p>http://www.molecularpain.com/content/4/1/12</p><p>Molecular Pain 2008;4():12-12.</p><p>Published online 16 Apr 2008</p><p>PMCID:PMC2359740.</p><p></p

Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HTreceptor signaling-0

in the absence and presence of 50 mM KCl and/or drugs. Drugs were present as indicated during "Pretreat" and "50 mM KCl" incubations but not during the "Basal" incubation. Data is presented as the mean ± S.E.M. and the number of wells tested is indicated in parentheses. An asterisk indicates a significant difference (p < 0.05) between the transmitter release from control cells and from cells treated with calcium channel blockers. Potassium-stimulated release of glutamate was inhibited by 1 μM ω-Aga TK, 1 μM ω-Cgtx GVIA and 1 μM nimodipine while basal glutamate release was not altered (Panel A). Potassium-stimulated release of CGRP was inhibited by 1 μM ω-Aga TK, 1 μM ω-Cgtx GVIA and 1 μM nimodipine while basal CGRP release was not altered (Panel B).<p><b>Copyright information:</b></p><p>Taken from "Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HTreceptor signaling"</p><p>http://www.molecularpain.com/content/4/1/12</p><p>Molecular Pain 2008;4():12-12.</p><p>Published online 16 Apr 2008</p><p>PMCID:PMC2359740.</p><p></p