title: Pannexin 3 functions as an ER Ca(2+) channel, hemichannel, and gap junction to promote osteoblast differentiation.
abstract: The pannexin proteins represent a new gap junction family. However, the cellular functions of pannexins remain largely unknown. Here, we demonstrate that pannexin 3 (Panx3) promotes differentiation of osteoblasts and ex vivo growth of metatarsals. Panx3 expression was induced during osteogenic differentiation of C2C12 cells and primary calvarial cells, and suppression of this endogenous expression inhibited differentiation. Panx3 functioned as a unique Ca(2+) channel in the endoplasmic reticulum (ER), which was activated by purinergic receptor/phosphoinositide 3-kinase (PI3K)/Akt signaling, followed by activation of calmodulin signaling for differentiation. Panx3 also formed hemichannels that allowed release of ATP into the extracellular space and activation of purinergic receptors with the subsequent activation of PI3K-Akt signaling. Panx3 also formed gap junctions and propagated Ca(2+) waves between cells. Blocking the Panx3 Ca(2+) channel and gap junction activities inhibited osteoblast differentiation. Thus, Panx3 appears to be a new regulator that promotes osteoblast differentiation by functioning as an ER Ca(2+) channel and a hemichannel, and by forming gap junctions.
authors.affiliation: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Andrew
authors.initials: A
authors.lastname: Doyle
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukumoto
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015220:Calcium Channels / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D017630:Connexins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D017629:Gap Junctions / Q000502:physiology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology
chemical_list: D015220:Calcium Channels; D017630:Connexins; C528477:pannexin 3 protein, mouse; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt