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Inhibition of Protein Kinases AKT and ERK1/2 Reduce the Carotid Body Chemoreceptor Response to Hypoxia in Adult Rats

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Arterial Chemoreceptors in Physiology and Pathophysiology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 860))

Abstract

The carotid body is the main mammalian oxygen-sensing organ regulating ventilation. Despite the carotid body is subjected of extensive anatomical and functional studies, little is yet known about the molecular pathways signaling the neurotransmission and neuromodulation of the chemoreflex activity. As kinases are molecules widely involved in motioning a broad number of neural processes, here we hypothesized that pathways of protein kinase B (AKT) and extracellular signal-regulated kinases ½ (ERK1/2) are implicated in the carotid body response to hypoxia. This hypothesis was tested using the in-vitro carotid body/carotid sinus nerve preparation (“en bloc”) from Sprague Dawley adult rats. Preparations were incubated for 60 min in tyrode perfusion solution (control) or containing 1 μM of LY294002 (AKT inhibitor), or 1 μM of UO-126 (ERK1/2 inhibitor). The carotid sinus nerve chemoreceptor discharge rate was recorded under baseline (perfusion solution bubbled with 5 % CO2 balanced in O2) and hypoxic (perfusion solution bubbled with 5 % CO2 balanced in N2) conditions. Compared to control, both inhibitors significantly decreased the normoxic and hypoxic carotid body chemoreceptor activity. LY294002- reduced carotid sinus nerve discharge rate in hypoxia by about 20 %, while UO-126 reduces the hypoxic response by 45 %. We concluded that both AKT and ERK1/2 pathways are crucial for the carotid body intracellular signaling process in response to hypoxia.

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References

  • Bairam A, Carroll JL (2005) Neurotransmitters in carotid body development. Respir Physiol Neurobiol 149(1–3):217–232

    PubMed  CAS  Google Scholar 

  • Balasubramanian S, Teissere JA, Raju DV et al (2004) Hetero-oligomerization between GABAA and GABAB receptors regulates GABAB receptor trafficking. J Biol Chem 279(18):18840–18850

    PubMed  CAS  Google Scholar 

  • Beaulieu JM, Sotnikova TD, Gainetdinov RR et al (2006) Paradoxical striatal cellular signaling responses to psychostimulants in hyperactive mice. J Biol Chem 281(43):32072–32080

    PubMed  CAS  Google Scholar 

  • Beitner-Johnson D, Rust RT, Hsieh TC, Millhorn DE (2001) Hypoxia activates Akt and induces phosphorylation of GSK-3 in PC12 cells. Cell Signal 13(1):23–27

    PubMed  CAS  Google Scholar 

  • Borowiec AS, Hague F, Harir N, Guenin S, Guerineau F, Gouilleux F, Roudbaraki M, Lassoued K, Ouadid-Ahidouch H (2007) IGF-1 activates hEAG K(+) channels through an Akt-dependent signaling pathway in breast cancer cells: role in cell proliferation. J Cell Physiol 212(3):690–701

    PubMed  CAS  Google Scholar 

  • Buckler KJ, Vaughan-Jones RD (1994) Effects of hypoxia on membrane potential and intracellular calcium in rat neonatal carotid body type I cells. J Physiol 476(3):423–428

    PubMed  CAS  PubMed Central  Google Scholar 

  • Chambard JC, Lefloch R, Pouyssegur J, Lenormand P (2007) ERK implication in cell cycle regulation. Biochim Biophys Acta 1773(8):1299–1310

    PubMed  CAS  Google Scholar 

  • Chan WS, Sideris A, Sutachan JJ et al (2013) Differential regulation of proliferation and neuronal differentiation in adult rat spinal cord neural stem/progenitors by ERK1/2, Akt, and PLCgamma. Front Mol Neurosci 6:23

    PubMed  PubMed Central  Google Scholar 

  • Cowen DS (2007) Serotonin and neuronal growth factors – a convergence of signaling pathways. J Neurochem 101(5):1161–1171

    PubMed  CAS  Google Scholar 

  • Dey N, Howell BW, De PK et al (2005) CSK negatively regulates nerve growth factor induced neural differentiation and augments AKT kinase activity. Exp Cell Res 307(1):1–14

    PubMed  CAS  Google Scholar 

  • Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8):606–619

    PubMed  CAS  Google Scholar 

  • Fang W, Gao G, Zhao H et al (2014) Role of the Akt/GSK-3beta/CRMP-2 pathway in axon degeneration of dopaminergic neurons resulting from MPP+ toxicity. Brain Res 1602:9–19

    PubMed  Google Scholar 

  • Ganfornina MD, Lopez-Barneo J (1991) Single K+ channels in membrane patches of arterial chemoreceptor cells are modulated by O2 tension. Proc Natl Acad Sci U S A 88(7):2927–2930

    PubMed  CAS  PubMed Central  Google Scholar 

  • Hirai K, Hayashi T, Chan PH, Zeng J, Yang GY, Basus VJ, James TL, Litt L (2004) P13K inhibition in neonatal rat brain slices during and after hypoxia reduces phospho-Akt and increases cytosolic cytochrome c and apoptosis. Brain Res Mol Brain Res 124(1):51–61

    PubMed  CAS  Google Scholar 

  • Joseph V, Niane LM, Bairam A (2012) Antagonism of progesterone receptor suppresses carotid body responses to hypoxia and nicotine in rat pups. Neuroscience 207:103–109

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kelly A, Lynch MA (2000) Long-term potentiation in dentate gyrus of the rat is inhibited by the phosphoinositide 3-kinase inhibitor, wortmannin. Neuropharmacology 39(4):643–651

    PubMed  CAS  Google Scholar 

  • Lee SM, Lee CT, Kim YW, Han SK, Shim YS, Yoo CG (2006) Hypoxia confers protection against apoptosis via PI3K/Akt and ERK pathways in lung cancer cells. Cancer Lett 242(2):231–238

    PubMed  CAS  Google Scholar 

  • Lopez-Barneo J, Lopez-Lopez JR, Urena J et al (1988) Chemotransduction in the carotid body: K+ current modulated by PO2 in type I chemoreceptor cells. Science 241(4865):580–582

    PubMed  CAS  Google Scholar 

  • Lopez-Barneo J, Pardal R, Ortega-Saenz P (2001) Cellular mechanism of oxygen sensing. Annu Rev Physiol 63:259–287

    PubMed  CAS  Google Scholar 

  • Man HY, Wang Q, Lu WY, Ju W, Ahmadian G, Liu L, D’Souza S, Wong TP, Taghibiglou C, Lu J, Becker LE, Pei L, Liu F, Wymann MP, MacDonald JF, Wang YT (2003) Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons. Neuron 38(4):611–624

    PubMed  CAS  Google Scholar 

  • Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274

    PubMed  CAS  PubMed Central  Google Scholar 

  • Montoro RJ, Urena J, Fernandez-Chacon R et al (1996) Oxygen sensing by ion channels and chemotransduction in single glomus cells. J Gen Physiol 107(1):133–143

    PubMed  CAS  Google Scholar 

  • Nishio H, Matsui K, Tsuji H, Tamura A, Suzuki K (2001) Immunolocalization of the mitogen-activated protein kinase signaling pathway in Hassall’s corpuscles of the human thymus. Acta Histochem 103(1):89–98

    PubMed  CAS  Google Scholar 

  • Opazo P, Watabe AM, Grant SG, O’Dell TJ (2003) Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms. J Neurosci 23(9):3679–3688

    PubMed  CAS  Google Scholar 

  • Porzionato A, Macchi V, Parenti A, De Caro R (2010) Extracellular signal-regulated kinase and phosphatidylinositol-3-kinase/AKT signalling pathways in the human carotid body and peripheral ganglia. Acta Histochem 112(4):305–316

    PubMed  Google Scholar 

  • Prabhakar NR, Overholt JL (2000) Cellular mechanisms of oxygen sensing at the carotid body: heme proteins and ion channels. Respir Physiol 122(2–3):209–221

    PubMed  CAS  Google Scholar 

  • Rosenblum K, Futter M, Jones M et al (2000) ERKI/II regulation by the muscarinic acetylcholine receptors in neurons. J Neurosci 20(3):977–985

    PubMed  CAS  Google Scholar 

  • Sanna PP, Cammalleri M, Berton F, Simpson C, Lutjens R, Bloom FE, Francesconi W (2002) Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region. J Neurosci 22(9):3359–3365

    PubMed  CAS  Google Scholar 

  • Su B, Karin M (1996) Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol 8(3):402–411

    PubMed  CAS  Google Scholar 

  • Taraviras S, Olli-Lahdesmaki T, Lymperopoulos A et al (2002) Subtype-specific neuronal differentiation of PC12 cells transfected with alpha2-adrenergic receptors. Eur J Cell Biol 81(6):363–374

    PubMed  CAS  Google Scholar 

  • Teng L, Kou C, Lu C et al (2014) Involvement of the ERK pathway in the protective effects of glycyrrhizic acid against the MPP+-induced apoptosis of dopaminergic neuronal cells. Int J Mol Med 34(3):742–748

    PubMed  CAS  PubMed Central  Google Scholar 

  • Urena J, Fernandez-Chacon R, Benot AR et al (1994) Hypoxia induces voltage-dependent Ca2+ entry and quantal dopamine secretion in carotid body glomus cells. Proc Natl Acad Sci U S A 91(21):10208–10211

    PubMed  CAS  PubMed Central  Google Scholar 

  • Waskiewicz AJ, Cooper JA (1995) Mitogen and stress response pathways: MAP kinase cascades and phosphatase regulation in mammals and yeast. Curr Opin Cell Biol 7(6):798–805

    PubMed  CAS  Google Scholar 

  • Weir EK, Lopez-Barneo J, Buckler KJ et al (2005) Acute oxygen-sensing mechanisms. N Engl J Med 353(19):2042–2055

    PubMed  CAS  PubMed Central  Google Scholar 

  • Wiese S, Jablonka S, Holtmann B et al (2007) Adenosine receptor A2A-R contributes to motoneuron survival by transactivating the tyrosine kinase receptor TrkB. Proc Natl Acad Sci U S A 104(43):17210–17215

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yoshii A, Constantine-Paton M (2014) Postsynaptic localization of PSD-95 is regulated by all three pathways downstream of TrkB signaling. Front Synaptic Neurosci 6:6

    PubMed  PubMed Central  Google Scholar 

  • Zhang X, Zhang Q, Tu J et al (2014) Prosurvival NMDA 2A receptor signaling mediates postconditioning neuroprotection in the hippocampus. Hippocampus 25(3):286–296

    PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank to Melanie Pelletier for her superb assistance and Richard Kinkead for fruitful discussions. J.S. is supported by grants from The Molly Towell Perinatal research Foundation (MTPRF), The Fonds de la Recherche Québec en Santé (FRQ-S: MOP-26974), and The Canadian Institute for Health Research (CIHR: MOP-130258).

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Authors and Affiliations

  1. Department of Pediatrics, Centre de Recherche de l’Hôpital St-François d’Assise (CR-SFA), Faculty of Medicine, Centre Hospitalier Universitaire de Québec (CHUQ), Laval University, 10, rue de l’Espinay, Québec, G1L 3L5, QC, Canada

    Pablo Iturri, Vincent Joseph & Jorge Soliz Ph.D.

  2. Molecular Biology and Biotechnology Institute, Universidad Mayor de San Andres, La Paz, Bolivia

    Pablo Iturri & Gloria Rodrigo

  3. Pediatric Department, Laval University, Research Center of Centre Hospitalier, Universitaire de Quebec, 10, rue de l’Espinay, Quebec City, QC, Canada

    Aida Bairam M.D., Ph.D.

  4. Centre de recherche du CHUQ, HSFA, 10, rue de l’Espinay, Québec, G1L 3L5, QC, Canada

    Aida Bairam M.D., Ph.D.

Authors
  1. Pablo Iturri
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  2. Vincent Joseph
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  3. Gloria Rodrigo
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  4. Aida Bairam M.D., Ph.D.
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  5. Jorge Soliz Ph.D.
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Corresponding author

Correspondence to Jorge Soliz Ph.D. .

Editor information

Editors and Affiliations

  1. Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Faculty of Medicine and Health, Leeds, United Kingdom

    Chris Peers

  2. College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

    Prem Kumar

  3. Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, Ohio, USA

    Christopher Wyatt

  4. Department of Pediatrics, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

    Estelle Gauda

  5. Department of Biology, McMaster University, Hamilton, Ontario, Canada

    Colin A. Nurse

  6. Institute for Integrative Physiology and Center for Systems Biology of O(2) Sensing Biological Sciences Division, University of Chicago, Chicago, Illinois, USA

    Nanduri Prabhakar

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© 2015 Springer International Publishing Switzerland

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Iturri, P., Joseph, V., Rodrigo, G., Bairam, A., Soliz, J. (2015). Inhibition of Protein Kinases AKT and ERK1/2 Reduce the Carotid Body Chemoreceptor Response to Hypoxia in Adult Rats. In: Peers, C., Kumar, P., Wyatt, C., Gauda, E., Nurse, C., Prabhakar, N. (eds) Arterial Chemoreceptors in Physiology and Pathophysiology. Advances in Experimental Medicine and Biology, vol 860. Springer, Cham. https://doi.org/10.1007/978-3-319-18440-1_31

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