Summary
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 supresses 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 suceptibility 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.
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References
Cohen G (1990) Monoamine oxidase and oxidative stress at dopaminergic synapses. J Neural Transm [Suppl] 32: 229–238
Erickson JD, Eiden LE, Hoffman BJ (1992) Expression cloning of a reserpine-sensitive vesicular monoamine transporter. Proc Natl Acad Sci USA 89: 10993–10997
Frohman MA (1991) RACE: rapid amplification of cDNA ends. In: Innis MA, Gelfand DH, Sninsky JJ, White TJ (eds) PCR protocols: a guide to methods and application. Academic Press, San Diego, pp 28–38
Gerlach M, Riederer P, Przuntek H, Youdim MBH (1991) MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease. Eur J Pharmacol Mol Pharmacol Sect 208: 273–286
Johnson R (1988) Accumulation of biological amines into chromaffine granules: a model for hormone and neurotransmitter transport. Physiol Rev 68: 232–307
Lesch KP, Wolozin BL, Murphy DL, Riederer P (1993a) Primary structure of the human platelet serotonin (5-HT) uptake site: identity with the brain 5-HT transporter. J Neurochem 60: 2319–2322
Lesch KP, Wolozin BL, Estler HC, Murphy DL, Riederer P (1993b) Isolation of a cDNA encoding the human brain serotonin transporter. J Neural Transm [Gen Sect] 91: 67–73
Liu Y, Peter D, Roghani A, Schuldiner S, Prive GG, Eisenberg D, Brecha N, Edwards RH (1992) A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell 70: 539–551
Rosenberg P (1988) Catecholamine in cerebral cortex in dissociated cell culture. J Neurosci 8: 2887–2894
Rudnick G, Steiner-Murdoch S, Fishkes H, Stern-Bach Y, Schuldiner S (1990) Energetics of reserpine binding and occlusion by the chromaffin granule biogenic amine transporter. Biochemistry 29: 603–608
Surratt CK, Persico AM, Yang XD, Edgar SR, Bird GS, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR (1993) A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modification, reveals chromosome 10 gene localization, and identifies Taq I RFLPs. FEBS Lett 318: 325–330
Tanner C, Langston J (1990) Do environmental toxins cause Parkinson's disease? A critical review. Neurology 40: 17–30
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Lesch, K.P., Gross, J., Wolozin, B.L. et al. Extensive sequence divergence between the human and rat brain vesicular monoamine transporter: Possible molecular basis for species differences in the susceptibility to MPP+ . J. Neural Transmission 93, 75–82 (1993). https://doi.org/10.1007/BF01244941
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DOI: https://doi.org/10.1007/BF01244941