title: Hedgehog Signaling Modulates the Release of Gliotransmitters from Cultured Cerebellar Astrocytes.
abstract: Sonic hedgehog (Shh), a member of the Hedgehog (Hh) family, plays essential roles in the development of the central nervous system. Recent studies suggest that the Hh signaling pathway also functions in mature astrocytes under physiological conditions. We first examined the expression of genes encoding Hh signaling molecules in the adult mouse cerebellum by in situ hybridization histochemistry. mRNA for Patched homolog 1 (Ptch1), a receptor for Hh family members, was expressed in S100β-positive astrocytes and Shh mRNA was expressed in HuC/D-positive neurons, implying that the Hh signaling pathway contributes to neuro-glial interactions. To test this hypothesis, we next examined the effects of recombinant SHH N-terminal protein (rSHH-N) on the functions of cultured cerebellar astrocytes. rSHH-N up-regulated Hh signal target genes such as Ptch1 and Gli-1, a key transcription factor of the Hh signaling pathway. Although activation of Hh signaling by rSHH-N or purmorphamine influenced neither glutamate uptake nor gliotransmitters release, inhibition of the Hh signaling pathway by cyclopamine, neutralizing antibody against SHH or intracellular Ca(2+) chelation decreased glutamate and ATP release from cultured cerebellar astrocytes. On the other hand, cyclopamine, neutralizing antibody against SHH or Ca(2+) chelator hardly affected D-serine secretion. Various kinase inhibitors attenuated glutamate and ATP release, while only U0126 reduced D-serine secretion from the astrocytes. These results suggested that the Hh signaling pathway sustains the release of glutamate and ATP and participates in neuro-glial interactions in the adult mouse brain. We also propose that signaling pathways distinct from the Hh pathway govern D-serine secretion from adult cerebellar astrocytes.
authors.affiliation: Department of Anatomy and Neuroscience, Faculty of Medicine, Nara Medical University, Kashihara City, Nara, 634-8521, Japan. okuda@naramed-u.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okuda
authors.affiliation: Department of Anatomy and Neuroscience, Faculty of Medicine, Nara Medical University, Kashihara City, Nara, 634-8521, Japan.
authors.forename: Kouko
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Anatomy and Neuroscience, Faculty of Medicine, Nara Medical University, Kashihara City, Nara, 634-8521, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Morita-Takemura
authors.affiliation: Department of Anatomy and Neuroscience, Faculty of Medicine, Nara Medical University, Kashihara City, Nara, 634-8521, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakahara
authors.affiliation: Department of Ophthalmology, Faculty of Medicine, Nara Medical University, Kashihara City, Nara, 634-8521, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Nochioka
authors.affiliation: Department of Anesthesiology, Faculty of Medicine, Nara Medical University, Kashihara City, Nara, 634-8521, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Shinjo
authors.affiliation: Department of Anesthesiology, Faculty of Medicine, Nara Medical University, Kashihara City, Nara, 634-8521, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Terada
authors.affiliation: Department of Anatomy and Neuroscience, Faculty of Medicine, Nara Medical University, Kashihara City, Nara, 634-8521, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Wanaka
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D018377:Neurotransmitter Agents
keywords: ATP; Astrocytes; Gliotransmitters; Glutamate; Hedgehog signaling