Nucleotide releasefrom glial cells plays important autocrine and paracrine signaling roles in the CMSand PNS. Recentstudies suggest that the non-lytic releaseof ATP from glial cells can either involve regulated exocytosis or efflux through nucleotide-permeable channels. Extracellular ATP acting onplasmalemmal ionotropic P2X and metabotropic P2Y receptors modulates neuronal activity, induces calcium transients in astrocytes and generatescritical intracellular second messengers implicated for instance in the development of gliosis following brain trauma and in the proliferation and migration of neural stem cells. Recently, we have obtained evidencethat neural progenitor cells display spontaneous calcium oscillations that are highly dependent on activation of P2Rs. Bath application of purinergic receptor antagonists or of the ATPdegrading enzyme apyrasepreventedthe occurrence of spontaneous calcium fluctuations. Moreover,blockade of P2Rs reduced the proliferation and the migration ratesof these progenitors. These results suggest that neural progenitors have the ability to release ATP,which then plays a crucial autocrine, paracrine signaling role during early CNS development.Although identification of pathways involvedon transmitter release from glial cells have been suggested for mature astrocytes, nothing is known about the developmental aspectsof the mechanism(s) by which ATP is released from precursors. Therefore, the goal of this grant application is to evaluate whether and at which stage of astrocyte development three of the putative pathways for transmitter release are functionally competent (excocytosis/secretion and diffusion through ionotropic P2XRs and connexin hemichannels) and to determine their contribution to calcium oscillations and cell migration. Immuocytochemical, biochemical and pharmacological approaches combined with luminescence and fluorecence imaging will be used to identify ATP release pathways. This identification is fundamental for the understanding of the signaling mechanisms ongoing during CNS development and repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052245-05
Application #
8018965
Study Section
Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
Program Officer
Morris, Jill A
Project Start
2007-01-15
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$320,277
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Velasquez, Stephani; Malik, Shaily; Lutz, Sarah E et al. (2016) Pannexin1 Channels Are Required for Chemokine-Mediated Migration of CD4+ T Lymphocytes: Role in Inflammation and Experimental Autoimmune Encephalomyelitis. J Immunol 196:4338-47
Cone, Angela C; Ambrosi, Cinzia; Scemes, Eliana et al. (2013) A comparative antibody analysis of pannexin1 expression in four rat brain regions reveals varying subcellular localizations. Front Pharmacol 4:6
Hanstein, Regina; Negoro, Hiromitsu; Patel, Naman K et al. (2013) Promises and pitfalls of a Pannexin1 transgenic mouse line. Front Pharmacol 4:61
Negoro, Hiromitsu; Lutz, Sarah E; Liou, Louis S et al. (2013) Pannexin 1 involvement in bladder dysfunction in a multiple sclerosis model. Sci Rep 3:2152
Lutz, Sarah E; González-Fernández, Estibaliz; Ventura, Juan Carlos Chara et al. (2013) Contribution of pannexin1 to experimental autoimmune encephalomyelitis. PLoS One 8:e66657
Scemes, Eliana; Spray, David C (2012) Extracellular Kýýý and astrocyte signaling via connexin and pannexin channels. Neurochem Res 37:2310-6
Scemes, Eliana (2012) Nature of plasmalemmal functional ""hemichannels"". Biochim Biophys Acta 1818:1880-3
Iacobas, S; Iacobas, D A; Spray, D C et al. (2012) The connexin43-dependent transcriptome during brain development: importance of genetic background. Brain Res 1487:131-9
Santiago, Marcelo F; Scemes, Eliana (2012) Neuroblast migration and P2Y(1) receptor mediated calcium signalling depend on 9-O-acetyl GD3 ganglioside. ASN Neuro 4:357-69
Suadicani, Sylvia O; Iglesias, Rodolfo; Wang, Junjie et al. (2012) ATP signaling is deficient in cultured Pannexin1-null mouse astrocytes. Glia 60:1106-16

Showing the most recent 10 out of 21 publications