YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
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Amino Acid Structure of Dopamine Transporter Responsible for Cocaine Binding

코카인 결합과 관련된 도파민 수송체의 아미노산 구조

  • 장미윤 (한양대학교 의과대학 생화학교실 및 정신건강연구소) ;
  • 전대준 (한양대학교 의과대학 생화학교실 및 정신건강연구소) ;
  • 오동렬 (국립전신병원) ;
  • 이용성 (한양대학교 의과대학 생화학교실 및 정신건강연구소) ;
  • 이상훈 (한양대학교 의과대학 생화학교실 및 정신건강연구소)
  • Published : 1999.12.01
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Abstract

Human and bovine dopamine transporters (DAT) demonstrate discrete functional differences in the dopamine (DA) transport and cocaine binding. The functional analyses on the chimeras of human and bovine DAT have revealed that the region from the $133^{rd}{\;}to{\;}186^{th}$ residue(encompassing the $3^{rd}$ trans-membrane domain (TM) is responsible for the substrate transport and cocaine binding. The present studies have been done to find out the specific amino acid(s) which is essential for the binding of cocaine to DAT by interchanging the amino acids in that region between human and bovine DAT. When isoleucine, the $152^{nd}$ residue of chimera B3 (bovine DAT sequence) was transformed back to valine, the human DAT residue at the identical position, the cocaine binding was remarkably recovered to 98% of the human DAT values. In addition, the cocaine binding of the human DAT was decreased by 57% by substituting isoleucine for valine at position 152. When isoleucine at position 152 of the chimera B3 was converted to the other amino acids to provide an possible molecular basis for the functional role of the $152^{nd}$ residue, only the conversion to alanine among acids tested significantly the cocaine by 34%, but these effect were not as much as those by the conversion to valine. In conclusion, valine at position 152 is a crucial amino acid for the interaction of cocaine to the DAT.

Keywords

References

  1. Annu. Rev. Neurosci. v.16 Neurotransmitter transporters. Recent progress Amara, S. G.;Kuhar, M. J.
  2. J. Neurosci. v.19 Transmembrane domaine I contributes to the permiation pathway for serotonin and ions in the serotonin transporter Barker, E. L.;Moore, K. R.;Rakhshan, F.;Blakely R. D.
  3. J Pharmacol Exp Ther v.251 Effect of cocaine and related drugs in nonhuman primates III. self-adminstration by squirrel monkeys Bergman, J.;Madras, B. K.;Johnson, S. E.;Spealman, R. D.
  4. Proc. Natl. Acad. Sci. USA v.91 Chimeric dopamine-norepinephrine transporters delineate structural domains influencing selectivity for catechoramines and 1-methyl-4-phenylpyridium Buck, K. J.;Amara, S. G.
  5. Mol. Pharmacol. v.48 Structural domains of catecholamine transporter chimeras involved in selective inhibition by antidepressants and psychomotor stimulants Buck, K. J.;Amara, S. G.
  6. J. Biol. Chem. v.272 The third transmembrane domain of the associated with substrated and cocain binding Chen, J. G.;Sachpatzidis A.;Rudnick G.
  7. Mol. Pharmacol. v.14 On the topology of the norepinephrine transport carrier in rat hypothalamus. The site of action of tricyclic uptake inhibitors DePaulis, T.;Kelder, D.;Ross, S. B.
  8. Mol. Pharmacol. v.42 no.3 Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter Giros, B.;Mestikawy, S.;Godinot, N.;Zheng, K.;Han, H.;Yang-Feng, T.;Caron, M. G.
  9. Trend in Pharm. Sci. v.14 Molecular characterization of dopamine transporter Giros, B.;Caron, M. G.
  10. J. Biol. Chem. v.269 Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine transproters Giros B.;Wang Y. M.;Suter S.;McLeskey S. B.;Pifl C.;Caron M. G.
  11. Prog. Neurobiol. v.34 Dopamine uptake: a review of progress in the last decade Horn, A. S.
  12. Handbook of psychopharmacology Iversen L. L.
  13. Crit. Rev. Biochem. v.22 Role of transmitter uptake mechanisms in synaptic neurotransmitter Iversen L. L.
  14. Proc. Natl. Acad. Sci. USA v.89 Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding Kitayama S.;Shimada S.;Xu H.;Markham L.;Donoban D. M.;Uhl G. R.
  15. Synapse v.15 Dopamine transporter mutants selectively enhance $MMP^+$ transport Kitayama S.;Wang J. B.;Uhl G.
  16. J. Neurochem. v.31 Synaptosomal transporter. a chloride dependence for choline, GABA, glycine, and several other compounds Kuhar, M. J.;Zarbin, M. A.
  17. Trends. Neurosci. v.14 The dopamine hypothesis of reinforcing properties of cocaine Kuhar M. J.;Ritz M. C.;Boja J. W.
  18. Ciba Found Symp. v.166 Molecular pharmacology of cocaine : a dopamine hypothesis and its implication Kuhar, M. J.
  19. Neurosci. Lett. v.214 Species differences in functions of dopamine transporter : paucity of $MPP^+$ uptake and cocaine binding in bovine dopamine transporter Lee, S. H.;Rhee, J.;Koh, J. K.l;Lee, Y. S.
  20. BBRC v.246 The region of dopamine transporter encompassing the $3^{rd}$ transmembrane domain is crucial for function Lee, S. H.;Kang, S. S.;Son, H.;Lee, Y. S.
  21. Mechanism of neuronal and extraneuronal transport of catecholamines Maxwell, R. A.;Ferris, R. M.;Burscu, J. E.
  22. Adv. Neurol. v.69 The dopamine transporter. the cloned target site of Parkinsonisminducing toxins and of drugs of abuse Pifl, C.;Giros, B.;Caron, M. G.
  23. Science v.237 Cocaine receptors on dopamine transporters are related to self-administration of cocaine Ritz, M. C.;Lamb, R. J.;Goldberg, S. R.;Kuhar, M. J.
  24. Science v.254 Cloning and expression of a cocaine-sensitive dopamine transporter complementary DNA Shimada, S.;Kitayama, S.;Lin, C. L.;Patel, A.;Nanthakumar, E.;Gregor, P.;Kuhar, M.;Uhl, G.
  25. J. Pharcol Exp Ther v.261 Effect of cocaine and related druge in nonhuman primates II. Stimulant effects on schedule-controlled behavior Spealman, R. D.;Madras, B. K.;Bergman, J.
  26. Trends Phrmacol. Sci. v.13 neurotransmitter transporters (plus) promissing new gene family Uhl, G. R.
  27. Trends Pharmacol. Sci. v.13 Transporter explosion : uptake on uptake Uhl, G. R.;Hartig, P. R.
  28. J. Neurochem. v.64 Dopamine transporter cysteine mutants : second extracellular loop cysteines are required for transporter expression Wang J. B.;Moriwaki A.;Uhl, G. R.