Cross‐talk interactions between spinal 5‐HT7 and 5‐HT2A receptors regulate serotonin‐induced phrenic motor plasticity

Abstract

Spinal serotonin receptors elicit respiratory motor plasticity, expressed as a long‐lasting enhancement in respiratory motor output; i.e. phrenic motor facilitation (pMF). While serotonin type 2 (5‐HT2A) and 7 (5‐HT7) receptors elicit phenotypically similar pMF, they do so via distinct cellular mechanisms. We previously demonstrated that low‐doses of serotonin give rise to pMF via 5‐HT2A receptors, but cross‐talk inhibition from 5‐HT7 receptors abolish pMF at higher doses indicating a “bell shaped” dose‐curve response for serotonin‐induced pMF. Thus, 5‐HT7 receptors both give rise to and constrain pMF. We have recently identified cAMP as a critical point of divergence for these contrasting effects. Specifically, 5‐HT7 receptors constrain 5‐HT2A receptor‐induced pMF via protein kinase A (PKA), but elicit pMF via exchange protein activated by cAMP (EPAC). Our working hypothesis is that selective activation of these divergent cAMP signaling pathways enables refined regulation of serotonin‐induced pMF. Further, we hypothesized that coincident 5‐HT2A receptor and EPAC activation would enhance pMF, whereas 5‐HT2A and PKA activation would constrain/eliminate pMF expression. In anesthesized, paralyzed and mechanically ventilated rats, intermittent intrathecal injections of a 5HT2A receptor agonist (DOI; 50.6 ± 3.1%; p ≤ 0.05) or EPAC activator (8pCPT; 6.2 ± 16.7%; p ≤ 0.05) alone elicited pMF; concurrent EPAC and 5‐HT2A receptor activation gave rise to additive pMF (110.9 ± 10.0%; p ≤ 0.05). In contrast, while PKA activator (6Bnz) alone gave rise to pMF (58.9 ± 8.6%; p ≤ 0.05), concurrent PKA and 5‐HT2A receptor activation abolished the capacity for either to elicit pMF (18.6 ± 6.5%; p ≥ 0.05). Thus, divergent cAMP signaling exerts contrasting effects on serotonin‐induced respiratory motor plasticity. Targeting of these distinct signaling pathways may be useful for treating diseases causing motor deficits, including spinal injury or motor neuron diseases.Support or Funding InformationSupported by NIH HL080209 and HL69024. DPF was supported by an Advanced Opportunity Fellowship at the University of Wisconsin, NIH fellowship (1F30HL126351‐010) and the Medical Scientist Training Program (NIH T32 GM008692).