Spinal 5‐HT7 Receptor Agonist Induced Phrenic Motor Facilitation Requires TrkB Signaling

Spinal activation of Gs-protein coupled 5-HT7 receptors with AS-19 (selective agonist) elicits long-lasting phrenic motor facilitation (PMF). Other Gs-coupled receptors (eg. adenosine A2A) induce PMF via trans-activation of TrkB, the high affinity BDNF receptor, activating AKT but not ERK MAP kinases (Golder et al., 2008). Since AKT is a "downstream" signaling molecule from TrkB, AKT activation may underlie PMF. We hypothesized that AS-19 elicits PMF by similar mechanisms to A2A-induced PMF, and requires TrkB and PI3 Kinase/AKT (not ERK) activation. In anesthetized, vagotomized and ventilated Sprague Dawley rats, intrathecal (C4) injections of a tyrosine kinase (k252a, 100 μM, 15 μl) or PI3 Kinase inhibitor (PI-828, 180 μM, 15 μl) were made prior to episodic AS-19 injections (10 μM, 5 μl; 3x5min). AS-19-induced PMF (80±11% baseline, 120 min post-injection) was inhibited by k252a (30±13%; n=5) and PI-828 (7±5%, n=4)(both p<0.001), which were not different from vehicle controls (14±10%, n=5). Although ERK inhibition (UO126, 100 μM; 15 μl, n=4) blocked early PMF (60min: 13±13%, p<0.05), late phase PMF was unaffected (120 min: 53±7%, nsd). Thus, 5-HT7 receptor-induced PMF requires TrkB and AKT activity, whereas ERK activity may be necessary only in early stages of the response. An understanding of PMF may guide development of novel strategies to treat ventilatory control disorders. (NIH HL80209 and F31 HL092785)