Inhibition of martentoxin on neuronal BK channel subtype (alpha+beta4): implications for a novel interaction model.
Martentoxin as a 37-residue peptide was capable of blocking large-conductance Ca(2+)-activated K(+) (BK) channels in adrenal medulla chromaffin cells. This study investigated the pharmacological discrimination of martentoxin on BK channel subtypes. The results showed that the iberiotoxin-insensitive neuronal BK channels (alpha+beta4) could be potently blocked by martentoxin (IC(50) = approximately 80 nM). In contrast, the iberiotoxin-sensitive BK channel consisting of only alpha-subunit was less sensitive to martentoxin. Distinctively, martentoxin inhibited neuronal BK channels (alpha+beta4) with a novel interaction mode. Two possible interaction sites of neuronal BK channels (alpha+beta4) might be responsible for the binding with martentoxin: one for trapping and the other located at the pore region for blocking. In addition, the inhibition of martentoxin on neuronal BK channels (alpha+beta4) depended on cytoplasmic Ca(2+) concentration. On the other hand, in vivo experiments from EEG recordings suggested that neuronal BK channels (alpha+beta4) were the primary target of martentoxin. Therefore, this research not only sheds light on a unique ligand for neuronal BK channels (alpha+beta4), but also highlights a novel model approach for the interaction between K(+) channels and specific-ligands.
Shi
Jian
J
Graduate School of the Chinese Academy of Sciences, Institute of Physiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China.
He
Hui Qiong
HQ
Zhao
Rong
R
Duan
Yan-Hong
YH
Chen
Jin
J
Chen
Ying
Y
Yang
Juan
J
Zhang
Jian Wei
JW
Shu
Xue Qin
XQ
Zheng
Ping
P
Ji
Yong Hua
YH
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D004569:Electroencephalography / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012604:Scorpion Venoms / Q000633:toxicity*; D013379:Substrate Specificity
D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D012604:Scorpion Venoms; C064719:iberiotoxin; D002118:Calcium