Multiple Pathways to Long-Lasting Phrenic Motor Facilitation

  • Erica A. Dale-Nagle
  • Michael S. Hoffman
  • Peter M. MacFarlane
  • Gordon S. Mitchell
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 669)


Plasticity is a hallmark of neural systems, including the neural system controlling breathing (Mitchell and Johnson 2003). Despite its biological and potential clinical significance, our understanding of mechanisms giving rise to any form of respiratory plasticity remains incomplete. Here we discuss recent advances in our understanding of cellular mechanisms giving rise to phrenic long-term facilitation (pLTF), a long-lasting increase in phrenic motor output induced by acute intermittent hypoxia (AIH). Recently, we have come to realize that multiple, distinct mechanisms are capable of giving rise to long-lasting phrenic motor facilitation (PMF); we use PMF as a general term that includes AIH-induced pLTF. It is important to begin an appreciation and understanding of these diverse pathways. Hence, we introduce a nomenclature based on upstream steps in the signaling cascade leading to PMF. Two pathways are featured here: the “Q” and the “S” pathways, named because they are induced by metabotropic receptors coupled to Gq and Gs proteins, respectively. These pathways appear to interact in complex and interesting ways, thus providing a range of potential responses in the face of changing physiological conditions or the onset of disease.


Cervical Spinal Cord Metabotropic Receptor Carotid Sinus Nerve Respiratory Motor Phrenic Motor Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Supported by NIH HL080209 and NS05777.


  1. Bach, K.B. and Mitchell, G.S. (1996) Hypoxia-induced long-term facilitation of respiratory activity is serotonin dependent. Respir. Physiol. 104, 251–260.CrossRefPubMedGoogle Scholar
  2. Baker-Herman, T.L. and Mitchell, G.S. (2002) Phrenic long-term facilitation requires spinal serotonin receptor activation and protein synthesis. J. Neurosci. 22, 6239–6246.PubMedGoogle Scholar
  3. Baker-Herman, T.L., Fuller, D.D., Bavis, R.W., Zabka, A.G., Golder, F.J., Doperalski, N.J., Johnson, R.A., Watters, J.J., and Mitchell, G.S. (2004) BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat. Neurosci. 7, 48–55.CrossRefPubMedGoogle Scholar
  4. Bocchiaro, C.M. and Feldman, J.L. (2004) Synaptic activity-dependent persistent plasticity in endogenously active mammalian motoneurons. Proc. Natl. Acad. Sci. USA 101, 4292–4295.CrossRefPubMedGoogle Scholar
  5. Bockaert, J., Claeysen, S., Bécamel, C., Dumuis, A., and Marin, P. (2006) Neuronal 5HT metabotropic receptors: Fine-tuning of their structure, signaling and roles in synaptic modulation. Cell Tissue Tes. 326, 553–572.CrossRefGoogle Scholar
  6. Dale-Nagle, E.A. and Mitchell, G.S. (2008a) Intrathecal administration of vascular endothelial growth factor (VEGF) elicits phrenic motor facilitation. FASEB J. 22, 1232–1236.Google Scholar
  7. Dale-Nagle, E.A. and Mitchell, G.S. (2008b) Cervical spinal erythropoietin elicits phrenic motor facilitation in rats . Soc. Neurosci. Abstr. 76.14/NN22.Google Scholar
  8. Fuller, D.D., Bach, K.B., Baker, T.L., Kinkead, R., and Mitchell, G.S. (2000) Long term facilitation of phrenic motor output. Respir. Physiol. 121, 135–146.CrossRefPubMedGoogle Scholar
  9. Fuller, D.D., Zabka, A., Baker, T.L., and Mitchell, G.S. (2001) Physiological and genomic consequences of intermittent hypoxia: Selected contribution: Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia. J. Appl. Physiol. 90, 2001–2006.PubMedGoogle Scholar
  10. Golder, F.J., Ranganathan, L., Satriotomo, I., Hoffman, M., Lovett-Barr, M.R., Watters, J.J., Baker-Herman, T.L., and Mitchell, G.S. (2008) Spinal adenosine A2a receptor activation elicits long-lasting phrenic motor facilitation. J. Neurosci. 28, 2033–2042.CrossRefPubMedGoogle Scholar
  11. Hayashi, F., Hinrichsen, C.F., and McCrimmon, D.R. (2003) Short-term plasticity of descending synaptic input to phrenic motoneurons in rats. J Physiol. 94(4), 1421–1430.Google Scholar
  12. Hoffman, M.S., Mahamed, S., Golder, F.J., and Mitchell, G.S. (2007) Adenosine A2A receptors constrain phrenic long term facilitation following acute intermittent hypoxia. FASEB. 918, 12.Google Scholar
  13. Hoffman, M.S. and Mitchell, G.S. (2008) Episodic spinal 5-HT7 receptor activation induces phrenic motor facilitation. FASEB J. 1232, 8.Google Scholar
  14. Kinkead, R. and Mitchell, G.S. (1999) Time-dependent hypoxic ventilatory responses in rats: Effects of ketanserin and 5 carboxamidotryptamine. Am. J. Physiol. 277(2 Pt2), R658–R666.PubMedGoogle Scholar
  15. Kishino, A. and Nakamaya, C. (2003) Enhancement of BDNF and activated ERK immunoreactivity in spinal motor neurons after peripheral administration of BDNF. Brain Res. 964, 56–66.CrossRefPubMedGoogle Scholar
  16. MacFarlane, P.M. and Mitchell, G.S. (2008) Respiratory long-term facilitation following intermittent hypoxia requires reactive oxygen species formation. Neuroscience 152, 189–197.CrossRefPubMedGoogle Scholar
  17. MacFarlane, P.M., Wilkerson, J.E., Lovett-Barr, M.R., and Mitchell, G.S. (2008) Reactive oxygen species and respiratory plasticity following intermittent hypoxia. Respir. Physiol. Neurobiol. 164, 263–271.CrossRefPubMedGoogle Scholar
  18. MacFarlane, P.M. and Mitchell, G.S. (2009) Episodic serotonin receptor activation elicits long-lasting phrenic motor facilitation by an NADPH oxidase-dependent mechanism . J. Physiol. 587(Pt 22), 5469–5481.CrossRefPubMedGoogle Scholar
  19. MacFarlane, P.M., Satriotomo, I., Windelborn, J.A., and Mitchell, G.S. (2009) NADPH oxidase activity is necessary for acute intermittent hypoxia-induced phrenic long-term facilitation. J Physiol. 587(Pt9), 1931–1942.CrossRefPubMedGoogle Scholar
  20. Mahamed, S. and Mitchell, G.S. (2007a) Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea? Exp. Physiol. 92, 27–37.CrossRefPubMedGoogle Scholar
  21. Mahamed, S. and Mitchell, G.S. (2007b) Facilitation of phrenic motor output following sustained hypocapnia in rats. FASEB J. 21, 918.16.Google Scholar
  22. McGuire, M., Liu, C., Cao, Y., and Ling, L. (2008) Formation and maintenance of ventilatory long- term facilitation require NMDA but not non-NMDA receptors in awake rats. J. Appl. Physiol. 105(3), 942–950.CrossRefPubMedGoogle Scholar
  23. Meszaros, J.G., Gonzalez, A.M., Endo-Mochizuki, Y., Villegas, S., Villarreal, F., and Brunton, L.L. (2000) Identification of G protein-coupled signaling pathways in cardiac fibroblasts: Cross talk between G(q) and G(s). Amer. J. Physiol. Cell. Physiol. 278, C154–C162.Google Scholar
  24. Millhorn, D.E., Eldridge, F.L., and Waldrop, T.G. (1980a) Prolonged stimulation of respiration by a new central neural mechanism. Respir. Physiol. 41, 87–103.CrossRefPubMedGoogle Scholar
  25. Millhorn, D.E., Eldridge, F.L., and Waldrop, T.G. (1980b) Prolonged stimulation of respiration by endogenous central serotonin. Respir. Physiol. 42, 171–188.CrossRefPubMedGoogle Scholar
  26. Mitchell, G.S. and Johnson, S.M. (2003) Neuroplasticity in respiratory motor control. J. Appl. Physiol. 94, 358–374.PubMedGoogle Scholar
  27. Mitchell, G.S. (2007) Respiratory plasticity following intermittent hypoxia: A guide for novel therapeutic approaches to ventilatory control disorders. In C. Gaultier (Ed.), Genetic basis for respiratory control disorders. New York: Springer Publishing Company.Google Scholar
  28. Neverova, N.V., Saywell, S.A., Nashold, L.F., Mitchell, G.S., and Feldman, J.L. (2007) Episodic stimulation of alpha1-adrenoreceptors induces protein kinase C-dependent persistent changes in motoneuronal excitability. J. Neurosci. 27, 4435–4442.CrossRefPubMedGoogle Scholar
  29. Roy, A.A., Nunn, C., Ming, H., Zou, M.X., Penninger, J., Kirshenbaum, L.A., Dixon, S.J., and Chidiac, P. (2006). Upregulation of endogenous RGS2 mediates cross desensitization between Gs and Gq signaling in osteoblasts. J. Biol. Chem. 281, 32684–32693.CrossRefPubMedGoogle Scholar
  30. Rhyzov, S., Goldstein, A.E., Biaggioni, I., and Feokistov, I. (2006) Cross-talk between G(s) and G(q)- coupled pathways in regulation of interleukin-4 by A(2B) adenosine receptors in human mast cells. Mol. Pharmacol. 70, 727–735.CrossRefGoogle Scholar
  31. Wilkerson, J.E., MacFarlane, P.M., Hoffman, M.S., and Mitchell, G.S. (2007) Respiratory plasticity following intermittent hypoxia: Roles of protein phosphatases and reactive oxygen species. Biochem. Soc. Trans. 35(Pt5), 1269–1272.PubMedGoogle Scholar
  32. Wilkerson, J.E., Satriotomo, I., Baker-Herman, T.L., Watters, J.J., and Mitchell, G.S. (2008) Okadaic acid-sensitive protein phosphatases constrain phrenic long-term facilitation after sustained hypoxia. J. Neurosci. 28, 2949–2458.CrossRefPubMedGoogle Scholar
  33. Wilkerson, J.E. and Mitchell, G.S. (2009) Daily intermittent hypoxia augments spinal BDNF levels, ERK phosphorylation and respiratory long-term facilitation. Exp. Neurol. 217(1), 116–123.CrossRefPubMedGoogle Scholar
  34. Zhang, Y., McGuire, M., White, D.P., and Ling, L. (2004) Serotonin receptor subtypes involved in vagus nerve stimulation-induced phrenic long-term facilitation in rats. Neurosci. Lett. 363(2), 108–111.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Erica A. Dale-Nagle
    • 1
  • Michael S. Hoffman
    • 1
  • Peter M. MacFarlane
    • 1
  • Gordon S. Mitchell
    • 1
  1. 1.Department of Comparative BiosciencesUniversity of WisconsinMadisonUSA

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