Description:
<jats:p>Serotonin type‐7 (5HT7) receptors in the cervical spinal cord elicit complex effects on respiratory motor activity. For example, intermittent 5HT7 receptor activation gives rise to long‐lasting phrenic motor facilitation (pMF); on the other hand, 5HT7 receptor activation constrains competing serotonin type‐2 induced pMF via protein kinase A (PKA)‐dependent “cross‐talk inhibition.” We hypothesized that divergent signaling pathways give rise to these distinct 5HT7 receptor actions. Specifically, whereas PKA regulates cross‐talk inhibition of 5HT2‐dependent pMF, a different cyclic AMP signaling pathway that requires exchange protein activated by cyclic AMP (EPAC) underlies 5HT7‐dependent pMF. Anesthetized, paralyzed and ventilated rats receiving intermittent 5HT7 receptor agonist injections (3x5uL; AS‐19) into the C4 intrathecal space expressed pMF for at least 90 minutes. This 5HT7‐induced pMF was abolished by pretreatment with a selective EPAC inhibitor (ESI‐05), but not a selective PKA inhibitor (KT‐5720). Further, an intrathecal EPAC activator (8‐pCPT‐2′‐O‐Me‐cAMP) is sufficient to elicit pMF. mTORC1 inhibition (rapamycin) abolished both 5HT7‐ and EPAC‐induced pMF. Thus, spinal 5HT7 receptors elicit pMF by a non‐canonical EPAC‐AKT‐mTORC1 pathway, and constrain alternate pathways to spinal respiratory motor plasticity via PKA signaling.</jats:p>