Hypoxic Ventilatory Response in Platelet-Derived Growth Factor Receptor-β–Knockout Mice

Tsunekawa, Saori; Ohi, Yoshiaki; Ikoma, Yoko; Sasahara, Masakiyo; Haji, Akira

doi:10.1254/jphs.09102fp

Cited by 10 publications

(7 citation statements)

References 30 publications

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“…1/2 and GSNOR 2/2 mice have minimal ventilatory roll-off (11), similar to that seen in mice deficient in PDGFR-b (5,6). The relationship between PDGFR-b, GSNOR, and the attenuation of roll-off in response to diminished expression of these genes is not known.…”

Section: Gsnormentioning

confidence: 74%

“…With sustained hypoxia, VM diminishes-a phenomenon known as ventilatory roll-off (1)(2)(3)(4). The mechanisms involved in roll-off include production of neurotransmitters inhibitory to respiration, such as g-amino-butyric acid and adenosine, as well as inhibition of NMDAR function via activation of platelet-derived growth factor (PDGF)-BB/PDGF receptor (PDGFR)-b signaling pathways (4)(5)(6).…”

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confidence: 99%

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Hypoxia-Induced Changes in Protein S-Nitrosylation in Female Mouse Brainstem

Palmer

deRonde

Brown-Steinke

et al. 2015

Am J Respir Cell Mol Biol

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Exposure to hypoxia elicits an increase in minute ventilation that diminishes during continued exposure (roll-off). Brainstem Nmethyl-D-aspartate receptors (NMDARs) and neuronal nitric oxide synthase (nNOS) contribute to the initial hypoxia-induced increases in minute ventilation. Roll-off is regulated by platelet-derived growth factor receptor-b (PDGFR-b) and S-nitrosoglutathione (GSNO) reductase (GSNOR). S-nitrosylation inhibits activities of NMDAR and nNOS, but enhances GSNOR activity. The importance of S-nitrosylation in the hypoxic ventilatory response is unknown. This study confirms that ventilatory roll-off is virtually absent in female GSNOR 1/2 and GSNO 2/2 mice, and evaluated the location of GSNOR in female mouse brainstem, and temporal changes in GSNOR activity, protein expression, and S-nitrosylation status of GSNOR, NMDAR (1, 2A, 2B), nNOS, and PDGFR-b during hypoxic challenge. GSNOR-positive neurons were present throughout the brainstem, including the nucleus tractus solitarius. Protein abundances for GSNOR, nNOS, all NMDAR subunits and PDGFR-b were not altered by hypoxia. GSNOR activity and S-nitrosylation status temporally increased with hypoxia. In addition, nNOS Snitrosylation increased with 3 and 15 minutes of hypoxia. Changes in NMDAR S-nitrosylation were detected in NMDAR 2B at 15 minutes of hypoxia. No hypoxia-induced changes in PDGFR-b Snitrosylation were detected. However, PDGFR-b phosphorylation increased in the brainstems of wild-type mice during hypoxic exposure (consistent with roll-off), whereas it did not rise in GSNOR 1/2 mice (consistent with lack of roll-off). These data suggest that: (1) S-nitrosylation events regulate hypoxic ventilatory response; (2) increases in S-nitrosylation of NMDAR 2B, nNOS, and GSNOR may contribute to ventilatory roll-off; and (3) GSNOR regulates PDGFR-b phosphorylation.Keywords: hypoxic ventilatory response; neuronal nitric oxide synthase; N-methyl-D-aspartate receptor; platelet-derived growth factor receptor-b; S-nitrosoglutathione reductase Clinical RelevanceThis article reports that the change in S-nitrosylation status of key brainstem proteins may underlie the roll-off phase of the hypoxic ventilatory response. This has potential clinical applications for understanding how mechanisms that affect S-nitrosothiol bioavailability (i.e., S-nitrosoglutathione reductase) play a role in central breathing disorders.

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Section: Gsnormentioning

confidence: 74%

mentioning

confidence: 99%

Hypoxia-Induced Changes in Protein S-Nitrosylation in Female Mouse Brainstem

Palmer

deRonde

Brown-Steinke

et al. 2015

Am J Respir Cell Mol Biol

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“…Inhibition of NMDA receptors within the NTS is thought to play a part in HVD, particularly via PDGF-beta signaling. This is due to observation of impaired HVD in mice heterozygous for a mutation in the PDGF-beta receptor as well as in mice lacking PDGF-beta expression in the brain (37,38). Other studies have been able to demonstrate that treatment with the NMDA receptor agonist ketamine can ameliorate several phenotypes present in mice lacking MeCP2 including disrupted breathing and apnea (34,39).…”

Section: Discussionmentioning

confidence: 99%

Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia

et al. 2020

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“…Pharmacological inhibition or diminished expression of PDGFRB abolishes the typical ventilatory decline (= ventilatory roll-off) that characteristically occurs with ongoing hypoxia. Similarly, this ventilatory roll-off disappears in conditional knockout of PDGFRB (Tsunekawa et al 2009). …”

Section: Role Of Pdgf In Synaptic Functionsmentioning

confidence: 96%

The Roles of PDGF in Development and During Neurogenesis in the Normal and Diseased Nervous System

Funa

Sasahara

2013

J Neuroimmune Pharmacol

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157

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The four platelet-derived growth factor (PDGF) ligands and PDGF receptors (PDGFRs), α and β (PDGFRA, PDGFRB), are essential proteins that are expressed during embryonic and mature nervous systems, i.e., in neural progenitors, neurons, astrocytes, oligodendrocytes, and vascular cells. PDGF exerts essential roles from the gastrulation period to adult neuronal maintenance by contributing to the regulation of development of preplacodal progenitors, placodal ectoderm, and neural crest cells to adult neural progenitors, in coordinating with other factors. In adulthood, PDGF plays critical roles for maintenance of many specific cell types in the nervous system together with vascular cells through controlling the blood brain barrier homeostasis. At injury or various stresses, PDGF modulates neuronal excitability through adjusting various ion channels, and affecting synaptic plasticity and function. Furthermore, PDGF stimulates survival signals, majorly PI3-K/Akt pathway but also other ways, rescuing cells from apoptosis. Studies imply an involvement of PDGF in dendrite spine morphology, being critical for memory in the developing brain. Recent studies suggest association of PDGF genes with neuropsychiatric disorders. In this review, we will describe the roles of PDGF in the nervous system, from the discovery to recent findings, in order to understand the broad spectrum of PDGF in the nervous system. Recent development of pharmacological and replacement therapies targeting the PDGF system is discussed.

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Hypoxic Ventilatory Response in Platelet-Derived Growth Factor Receptor-β–Knockout Mice

Cited by 10 publications

References 30 publications

Hypoxia-Induced Changes in Protein S-Nitrosylation in Female Mouse Brainstem

Hypoxia-Induced Changes in Protein S-Nitrosylation in Female Mouse Brainstem

Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia

The Roles of PDGF in Development and During Neurogenesis in the Normal and Diseased Nervous System

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