Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling.
Spinal serotonin type 7 (5-HT7) receptors elicit complex effects on motor activity. Whereas 5-HT7 receptor activation gives rise to long-lasting phrenic motor facilitation (pMF), it also constrains 5-HT2 receptor-induced pMF via "cross-talk inhibition." We hypothesized that divergent cAMP-dependent signaling pathways give rise to these distinct 5-HT7 receptor actions. Specifically, we hypothesized that protein kinase A (PKA) mediates cross-talk inhibition of 5-HT2 receptor-induced pMF whereas 5-HT7 receptor-induced pMF results from exchange protein activated by cAMP (EPAC) signaling. Anesthetized, paralyzed, and ventilated rats receiving intrathecal (C4) 5-HT7 receptor agonist (AS-19) injections expressed pMF for >90 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-HT7 receptor- and EPAC-induced pMF, demonstrating that spinal 5-HT7 receptors elicit pMF by an EPAC-mTORC1 signaling pathway. Thus 5-HT7 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.
Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin; and.
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DP
Fields
Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin; and.
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SR
Springborn
Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin; and Department of Physical Therapy and McKnight Brain Institute, University of Florida, Gainesville, Florida gsmitche@phhp.ufl.edu.
G S
GS
Mitchell
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology; D046912:Multiprotein Complexes / Q000378:metabolism*; D009473:Neuronal Plasticity; D010791:Phrenic Nerve / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D011985:Receptors, Serotonin / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D046912:Multiprotein Complexes; C526973:Rapgef3 protein, rat; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases
5-HT7; exchange protein activated by cAMP; mTOR; motor neuron; neuroplasticity; phrenic nerve; protein kinase A; rapamycin; receptor; respiratory plasticity; spinal cord