Multiple pathways to long-lasting phrenic motor facilitation

Abstract

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.

Figure 1

Representative traces of phrenic motor facilitation (PMF) induced by: a. acute intermittent hypoxia (i.e. pLTF, the Q pathway; tracing from Mitchell, 2007); b. episodic intrathecal α1 adrenergic agonist administration (phenylephrine; i.e. Q pathway, MacFar-lane and Mitchell, unpublished); and c. episodic intrathecal 5-HT7 receptor agonist administration (AS19; i.e. S pathway, Hoffman and Mitchell, 2008). Arrows indicate hypoxic episodes or agonist injections. Progressive increase in integrated phrenic burst amplitude above baseline (dotted white line) is PMF (brackets on right).

Figure 2

Current working model of convergent pathways to PMF. The “Q” pathway (left, black arrows) is elicited by intermittent activation of Gq-coupled metabotropic receptors (e.g. 5-HT2 or α1). Subsequent activation of protein kinase C (PKC) initiates new BDNF synthesis and increases NADPH oxidase (NOX) activity. BDNF activates TrkB and then ERK MAP kinases (pERK). Protein phosphatases (PP2/5) normally constrain pLTF, but are regulated via NADPH oxidase (NOX) dependent ROS formation. The “S” pathway (right; white arrows) is elicited by Gs-coupled metabotropic receptors (eg. 5-HT7 and A2A) coupled to protein kinase A (PKA). PKA may induce new synthesis of an immature TrkB isoform, which auto-phosphorylates and signals from inside the cell via Akt activation (pAkt). We postulate that both pERK and pAkt phosphorylate glutamate receptors, thereby giving rise to greater synaptic strength and PMF. We cannot rule out changes in motor neuron excitability as a cause of PMF, for example via membrane insertion of ion channels.