Extensive sequence divergence between the human and rat brain vesicular monoamine transporter: possible molecular basis for species differences in the susceptibility to MPP+.
A cDNA encoding the human brain vesicular monoamine transporter (VMT) was isolated and sequenced using PCR. The cDNA contains an open reading frame encoding a hydrophobic polypeptide of 514 amino acids with twelve membrane spanning segments, a calculated molecular weight of 55,709 Da, and an estimated isoelectrical point of 5.62. A structurally identical transporter is expressed in human platelets. Two intraplasmatic consensus phosphorylation sites of cAMP-dependent protein kinase recognition and two potential protein kinase C phosphorylation sites may be central to the regulation of the VMT. Although the human brain VMT is 90.7% homologous to the rat protein, an extensive sequence divergence occurs in the large luminal loop located between the first two transmembrane domains. This loop displays a remarkably reduced homology of 64.0% with several deletions and insertions, although four putative glycosylation sites are conserved. Since functional vesicular monoamine transport suppresses MPP+ toxicity and sequence divergence in the large luminal loop of the VMT expressed in rat brain and adrenal medulla may play a role in differential neurotoxic effects of MPP+, our findings indicate one possible molecular basis for the substantial species differences in the susceptibility to MPP+ demonstrated among humans, non-human primates, and rodents. They are also likely to facilitate molecular pharmacologic and genetic investigations of the human VMT in neurodegenerative disorders.
Department of Psychiatry, University of Würzburg, Federal Republic of Germany.
K P
KP
Lesch
J
J
Gross
B L
BL
Wolozin
D L
DL
Murphy
P
P
Riederer
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001792:Blood Platelets / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004351:Drug Resistance; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data; D009479:Neuropeptides; D015345:Oligonucleotide Probes / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats / Q000235:genetics*; D017385:Sequence Homology; D013045:Species Specificity; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D006023:Glycoproteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D015345:Oligonucleotide Probes; D011726:Pyridinium Compounds; C493452:SLC18A2 protein, human; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C026560:1-(4-methoxyphenyl)pyridinium; D004247:DNA