PMID- 23850591 OWN - NLM STAT- MEDLINE DCOM- 20140404 LR - 20211021 IS - 1873-7544 (Electronic) IS - 0306-4522 (Print) IS - 0306-4522 (Linking) VI - 250 DP - 2013 Oct 10 TI - Spinal 5-HT7 receptors and protein kinase A constrain intermittent hypoxia-induced phrenic long-term facilitation. PG - 632-43 LID - S0306-4522(13)00574-5 [pii] LID - 10.1016/j.neuroscience.2013.06.068 [doi] AB - Phrenic long-term facilitation (pLTF) is a form of serotonin-dependent respiratory plasticity induced by acute intermittent hypoxia (AIH). pLTF requires spinal Gq protein-coupled serotonin-2 receptor (5-HT2) activation, new synthesis of brain-derived neurotrophic factor (BDNF) and activation of its high-affinity receptor, TrkB. Intrathecal injections of selective agonists for Gs protein-coupled receptors (adenosine 2A and serotonin-7; 5-HT7) also induce long-lasting phrenic motor facilitation via TrkB "trans-activation." Since serotonin released near phrenic motor neurons may activate multiple serotonin receptor subtypes, we tested the hypothesis that 5-HT7 receptor activation contributes to AIH-induced pLTF. A selective 5-HT7 receptor antagonist (SB-269970, 5mM, 12 mul) was administered intrathecally at C4 to anesthetized, vagotomized and ventilated rats prior to AIH (3, 5-min episodes, 11% O2). Contrary to predictions, pLTF was greater in SB-269970 treated versus control rats (80 +/- 11% versus 45 +/- 6% 60 min post-AIH; p<0.05). Hypoglossal LTF was unaffected by spinal 5-HT7 receptor inhibition, suggesting that drug effects were localized to the spinal cord. Since 5-HT7 receptors are coupled to protein kinase A (PKA), we tested the hypothesis that PKA inhibits AIH-induced pLTF. Similar to 5-HT7 receptor inhibition, spinal PKA inhibition (KT-5720, 100 muM, 15 mul) enhanced pLTF (99 +/- 15% 60 min post-AIH; p<0.05). Conversely, PKA activation (8-br-cAMP, 100 muM, 15 mul) blunted pLTF versus control rats (16 +/- 5% versus 45 +/- 6% 60 min post-AIH; p<0.05). These findings suggest a novel mechanism whereby spinal Gs protein-coupled 5-HT7 receptors constrain AIH-induced pLTF via PKA activity. CI - Copyright (c) 2013 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Hoffman, M S AU - Hoffman MS AD - Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA. FAU - Mitchell, G S AU - Mitchell GS LA - eng GR - R01 HL080209/HL/NHLBI NIH HHS/United States GR - T32 HL007654/HL/NHLBI NIH HHS/United States GR - T32 GM008692/GM/NIGMS NIH HHS/United States GR - R01HL80209/HL/NHLBI NIH HHS/United States GR - F31 HL092785/HL/NHLBI NIH HHS/United States GR - T32 HL07654/HL/NHLBI NIH HHS/United States GR - F31- HL092785/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20130711 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Carbazoles) RN - 0 (Enzyme Inhibitors) RN - 0 (Phenols) RN - 0 (Pyrroles) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (Receptors, Serotonin) RN - 0 (SB 269970) RN - 0 (Serotonin Antagonists) RN - 0 (Sulfonamides) RN - 0 (serotonin 7 receptor) RN - 58HV29I28S (KT 5720) RN - EC 1.6.3.- (NADPH Oxidases) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM MH - Animals MH - Arterial Pressure/drug effects/physiology MH - Blood Gas Analysis MH - Carbazoles/pharmacology MH - Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/*metabolism MH - Data Interpretation, Statistical MH - Enzyme Inhibitors/pharmacology MH - Hypoglossal Nerve/physiology MH - Hypoxia/enzymology/*metabolism MH - Injections, Spinal MH - Long-Term Potentiation/*physiology MH - Male MH - NADPH Oxidases/metabolism MH - Phenols/pharmacology MH - Phrenic Nerve/*physiology MH - Pyrroles/pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Receptor Cross-Talk/physiology MH - Receptors, G-Protein-Coupled/metabolism MH - Receptors, Serotonin/drug effects/*metabolism MH - Serotonin Antagonists/pharmacology MH - Spinal Cord/drug effects/enzymology/*metabolism MH - Sulfonamides/pharmacology PMC - PMC3833466 MID - NIHMS504591 OTO - NOTNLM OT - AIH OT - ANOVA OT - BDNF OT - MAP OT - NADPH OT - PETCO(2) OT - PKA OT - ROS OT - acute intermittent hypoxia OT - analysis of variance OT - brain-derived neurotrophic factor OT - end-tidal carbon dioxide partial pressures OT - hypoxia OT - long-term facilitation OT - mean arterial pressures OT - motor neuron OT - nicotinamide adenine dinucleotide phosphate OT - pLTF OT - pMF OT - phrenic OT - phrenic long-term facilitation OT - phrenic motor facilitation OT - protein kinase A OT - reactive oxygen species OT - respiratory control OT - respiratory plasticity EDAT- 2013/07/16 06:00 MHDA- 2014/04/05 06:00 PMCR- 2014/10/10 CRDT- 2013/07/16 06:00 PHST- 2013/02/28 00:00 [received] PHST- 2013/06/21 00:00 [revised] PHST- 2013/06/29 00:00 [accepted] PHST- 2013/07/16 06:00 [entrez] PHST- 2013/07/16 06:00 [pubmed] PHST- 2014/04/05 06:00 [medline] PHST- 2014/10/10 00:00 [pmc-release] AID - S0306-4522(13)00574-5 [pii] AID - 10.1016/j.neuroscience.2013.06.068 [doi] PST - ppublish SO - Neuroscience. 2013 Oct 10;250:632-43. doi: 10.1016/j.neuroscience.2013.06.068. Epub 2013 Jul 11.