Past-A, a novel proton-associated sugar transporter, regulates glucose homeostasis in the brain.
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.
Shimokawa
Noriaki
N
Molecular Signaling Group, Ludwig Institute for Cancer Research, Uppsala, S-75124, Sweden. simokawa@med.gunma-u.ac.jp
Okada
Junichi
J
Haglund
Kaisa
K
Dikic
Ivan
I
Koibuchi
Noriyuki
N
Miura
Mitsuhiko
M
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
D002352:Carrier Proteins; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; C468273:Slc45a1 protein, rat; D002245:Carbon Dioxide; D005947:Glucose