title: Spinal 5-HT7 receptors and protein kinase A constrain intermittent hypoxia-induced phrenic long-term facilitation.
abstract: 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 μl) 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 μM, 15 μl) enhanced pLTF (99 ± 15% 60 min post-AIH; p<0.05). Conversely, PKA activation (8-br-cAMP, 100 μM, 15 μl) 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.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Hoffman
authors.forename: G S
authors.initials: GS
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects / Q000502:physiology; D001784:Blood Gas Analysis; D002227:Carbazoles / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007002:Hypoglossal Nerve / Q000502:physiology; D000860:Hypoxia / Q000201:enzymology / Q000378:metabolism*; D007278:Injections, Spinal; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D010791:Phrenic Nerve / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D010636:Phenols; D011758:Pyrroles; D043562:Receptors, G-Protein-Coupled; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor; C057416:KT 5720; D019255:NADPH Oxidases; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: AIH; ANOVA; BDNF; MAP; NADPH; PETCO(2); PKA; ROS; acute intermittent hypoxia; analysis of variance; brain-derived neurotrophic factor; end-tidal carbon dioxide partial pressures; hypoxia; long-term facilitation; mean arterial pressures; motor neuron; nicotinamide adenine dinucleotide phosphate; pLTF; pMF; phrenic; phrenic long-term facilitation; phrenic motor facilitation; protein kinase A; reactive oxygen species; respiratory control; respiratory plasticity