Specificity of human and rat orthologs of the concentrative nucleoside transporter, SPNT

被引:18
作者
Gerstin, KM [1 ]
Dresser, MJ [1 ]
Giacomini, KM [1 ]
机构
[1] Univ Calif San Francisco, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA
关键词
two-electrode voltage clamp; concentrative; sodium dependent; guanosine; adenosine;
D O I
10.1152/ajprenal.00274.2001
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
To understand the roles that nucleoside transporters play in the in vivo distribution of clinically important nucleoside analogs, the substrate specificity of each transporter isoform should be determined. In the present work, we studied the substrate specificities of the human and rat orthologs of the Na+-dependent purine-selective nucleoside transporter (SPNT; concentrative nucleoside transporter 2), for nucleosides, nucleobases, and base- and ribose-modified nucleoside analogs. The two-electrode voltage-clamp technique in Xenopus laevis oocytes expressing these transporters was used. Purine nucleosides and uridine induced currents in oocytes expressing rat SPNT (rSPNT) or human SPNT1 (hSPNT1). The rank order of magnitude of nucleoside-induced currents was guanosine > uridine > adenosine > inosine and guanosine > uridine > inosine > adenosine for rSPNT- and hSPNT1-expressing oocytes, respectively. Uridine analogs (modified at the 5-position of the base) induced little or no current, suggesting that these compounds are only poorly transported by either transporter. Cladribine induced currents in oocytes expressing rSPNT (K-0.5 = 57 +/- 12 muM) but not hSPNT1. The ribose-modified nucleoside analogs, adenine arabinoside, and 2', 3'-dideoxyadenosine induced currents in rSPNT- expressing, but not in hSPNT1-expressing, oocytes. These data suggest that there are notable species differences in the specificity of SPNT for synthetic nucleoside analogs.
引用
收藏
页码:F344 / F349
页数:6
相关论文
共 32 条
[1]   VOLTAGE-CLAMP STUDIES OF THE NA+/GLUCOSE COTRANSPORTER CLONED FROM RABBIT SMALL-INTESTINE [J].
BIRNIR, B ;
LOO, DDF ;
WRIGHT, EM .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 1991, 418 (1-2) :79-85
[2]   PRIMARY STRUCTURE AND FUNCTIONAL EXPRESSION OF A CDNA-ENCODING THE BILE CANALICULAR, PURINE-SPECIFIC NA+-NUCLEOSIDE COTRANSPORTER [J].
CHE, MX ;
ORTIZ, DF ;
ARIAS, IM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (23) :13596-13599
[3]  
Dresser MJ, 2000, DRUG METAB DISPOS, V28, P1135
[4]  
Dunwiddie TV, 1997, J NEUROSCI, V17, P7673
[5]   Molecular cloning of a Na+-dependent nucleoside transporter from rabbit intestine [J].
Gerstin, KM ;
Dresser, MJ ;
Wang, J ;
Giacomini, KM .
PHARMACEUTICAL RESEARCH, 2000, 17 (08) :906-910
[6]   EXPRESSION OF A RENAL NA+-NUCLEOSIDE COTRANSPORT SYSTEM (N2) IN XENOPUS-LAEVIS OOCYTES [J].
GIACOMINI, KM ;
MARKOVICH, D ;
WERNER, A ;
BIBER, J ;
WU, XC ;
MURER, H .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 1994, 427 (3-4) :381-383
[7]  
HUANG QQ, 1994, J BIOL CHEM, V269, P17757
[8]   A novel subunit for Shal K+ channels radically alters activation and inactivation [J].
Jegla, T ;
Salkoff, L .
JOURNAL OF NEUROSCIENCE, 1997, 17 (01) :32-44
[9]   Differentiation of substrate and nonsubstrate inhibitors of the high-affinity, sodium-dependent glutamate transporters [J].
Koch, HP ;
Kavanaugh, MP ;
Esslinger, CS ;
Zerangue, N ;
Humphrey, JM ;
Amara, SG ;
Chamberlin, AR ;
Bridges, RJ .
MOLECULAR PHARMACOLOGY, 1999, 56 (06) :1095-1104
[10]   NA+-DEPENDENT AND K+-DEPENDENT URIDINE TRANSPORT IN RAT RENAL BRUSH-BORDER MEMBRANE-VESICLES [J].
LEE, CW ;
CHEESEMAN, CI ;
JARVIS, SM .
BIOCHIMICA ET BIOPHYSICA ACTA, 1988, 942 (01) :139-149