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Fig. 6 | Journal of Neuroinflammation

Fig. 6

From: Systemic inflammation suppresses spinal respiratory motor plasticity via mechanisms that require serine/threonine protein phosphatase activity

Fig. 6

Proposed mechanism of LPS-induced inhibition of moderate acute intermittent hypoxia-induced phrenic long-term facilitation (pLTF). Moderate acute intermittent hypoxia (mAIH) induces serotonin (5-HT) release from serotonergic projections near spinal phrenic motor neurons. Serotonin activates phrenic 5-HT type 2 receptors, initiating a signaling cascade that phosphorylates ERK 1/2 MAPK and induces downstream BDNF protein synthesis. Newly synthesized BDNF signals through its high affinity receptor, TrKB, leading to increased excitatory respiratory drive onto phrenic motor neurons. Physiologically, enhanced excitatory drive is manifested as a long-lasting enhancement of phrenic motor output (i.e., pLTF). In our proposed model, systemic LPS leads to activation of inflammatory mechanisms within the central nervous system, phosphorylating (activating) p38 MAPK within phrenic motor neurons. Phospho-p38 MAPK activates okadaic acid-sensitive serine/threonine protein phosphatases (PP1/2A) that may act on 5-HT2 signaling at multiple sites. We propose that PP1/2A negatively regulates 5-HT2 signaling at the MEK and/or ERK 1/2 activation loop. Inhibition of PP1/2A activity with okadaic acid in LPS-treated rats permits 5-HT2-mediated MEK-ERK1/2 signaling, restoring mAIH-induced pLTF. Broken lines: undefined inhibitory feedback site at or below MEK level. Broken arrows: hypothesized pathway with unknown precise mechanism in the proposed model. Phosphorylation of the target molecule is marked by the letter P

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