Overexpression of human MRP1 in neurons causes resistance to antiepileptic drugs in Drosophila seizure mutants.
Multidrug resistance-associated protein 1 (MRP1), an efflux multidrug transporter, was shown to be elevated in both glia and neurons in seizure focus in refractory epilepsy patients. Up-regulation of MRP1 and other multidrug transporters in perivascular astrocytes was suggested to cause resistance to antiepileptic drugs (AEDs) by reducing the concentration of AEDs at the epileptogenic areas. However, it is not known whether the up-regulation of MRP1 in neurons can cause resistance to AEDs, such as sodium phenytoin (PHT) and valproic acid (VPA). PHT inhibits voltage-gated sodium channel (VGSC) by occluding it, but whether PHT enters the channel through its inner or outer pore is not known. The authors overexpressed human MRP1 protein only in neurons in a Drosophila genetic seizure model, bang senseless (bss) mutants. The authors found that overexpression of MRP1 blocked the attenuation of the seizure behavior of bss mutants by acute and chronic application of PHT, and by chronic application of VPA. Conversely, overexpression of MRP1 in neurons increased the tolerance of bss flies to high-dosage PHT and VPA. Thus, up-regulation of MRP1 expression only in neurons causes resistance to AED in seizure flies. Moreover, the current data suggest that PHT enters VGSC through its inner pore.
Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Guan-Shui
GS
Bao
Wen-An
WA
Wang
Tian-Zhe
TZ
Wang
Jian-Kang
JK
Huang
Hua
H
He
Zhenguo
Z
Liu
Fu-De
FD
Huang
D000818:Animals; D030801:Animals, Genetically Modified; D000927:Anticonvulsants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism
D000927:Anticonvulsants; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1