title: Past-A, a novel proton-associated sugar transporter, regulates glucose homeostasis in the brain.
abstract: The ventral medullary surface (VMS) of the medulla oblongata is known to be the site of the central chemosensitive neurons in mammals. These neurons sense excess H+/CO2 dissolved in the CSF and induce hyperventilation. To elucidate the mechanism of neuronal cell adaptation to changes of H+/CO2, we screened for hypercapnia-induced genes in the VMS. Here, we report cloning and characterization of a novel gene called proton-associated sugar transporter-A (Past-A), which is induced in the brain after hypercapnia and mediates glucose uptake along the pH gradient. Past-A comprises 751 amino acid residues containing 12 membrane-spanning helices, several conserved sugar transport motifs, three proline-rich regions, and leucine repeats. Past-A transcript was expressed predominantly in the brain. Moreover, the Past-A-immunoreactive neural cells were found in the VMS of the medulla oblongata, and the number of immunoreactive cells was increased by hypercapnic stimulation. Transient transfection of Past-A in COS-7 cells leads to the expression of a membrane-associated 82 kDa protein that possesses a glucose transport activity. The acidification of extracellular medium facilitated glucose uptake, whereas the addition of carbonyl cyanide m-chlorophenylhydrazone, a protonophore, inhibited glucose import. Together, our results indicate that Past-A is a brain-specific glucose transporter that may represent an adaptation mechanism regulating sugar homeostasis in neuronal cells after hypercapnia.
authors.affiliation: Molecular Signaling Group, Ludwig Institute for Cancer Research, Uppsala, S-75124, Sweden. simokawa@med.gunma-u.ac.jp
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimokawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Okada
authors.forename: Kaisa
authors.initials: K
authors.lastname: Haglund
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Koibuchi
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Miura
mesh_terms: D000280:Administration, Inhalation; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D015152:Blotting, Northern; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019556:COS Cells / Q000378:metabolism; D002245:Carbon Dioxide / Q000008:administration & dosage; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002628:Chemoreceptor Cells / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism* / Q000493:pharmacokinetics; D006706:Homeostasis / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D006935:Hypercapnia / Q000139:chemically induced / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D010802:Phylogeny; D011149:Pons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002352:Carrier Proteins; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; C468273:Slc45a1 protein, rat; D002245:Carbon Dioxide; D005947:Glucose