TY - JOUR
T1 - Iptakalim as a human nicotinic acetylcholine receptor antagonist
AU - Hu, Jun
AU - Lindenberger, Kari
AU - Hu, Gang
AU - Wang, Hai
AU - Lukas, Ronald J.
AU - Wu, Jie
PY - 2006/2
Y1 - 2006/2
N2 - Nicotinic acetylcholine receptors (nAChRs) play many critical roles in nervous system function and have been implicated in a variety of diseases. Drugs acting at nAChRs, perhaps in nAChR subtype-selective manners, can be used to dissect receptor function and perhaps as medications. In the present study, we used patch-clamp whole-cell recording and pharmacological manipulations to evaluate effects of iptakalim hydrochloride (Ipt), which is a drug reported to act as an ATP-sensitive potassium (KATP) channel opener, on selected human nAChRs heterologously expressed in the native nAChR-null SH-EP1 human epithelial cell line. Ipt reduced both peak and steadystate whole-cell current amplitudes mediated by human α4β2-nAChRs in response to nicotinic agonists. It also accelerated current decay, caused a decline in apparent efficacy of agonists, and acted in voltage- and use-dependent manners at α4β2-nAChRs. These findings and the inability of Ipt to block radiolabeled epibatidine binding to α4α2-nAChRs suggest a noncompetitive mechanism of antagonism. Other studies discount effects of Ipt on nAChR internalization or involvement of KATP channels in Ipt-induced inhibition of α4β2-nAChR function. By comparison, α7-nAChRs were less sensitive than α4β2-nAChRs to Ipt acting as an antagonist. Thus, α4β2-nAChRs are among the molecular targets of Ipt, which has utility as a tool in functional characterization and pharmacological profiling of nAChRs.
AB - Nicotinic acetylcholine receptors (nAChRs) play many critical roles in nervous system function and have been implicated in a variety of diseases. Drugs acting at nAChRs, perhaps in nAChR subtype-selective manners, can be used to dissect receptor function and perhaps as medications. In the present study, we used patch-clamp whole-cell recording and pharmacological manipulations to evaluate effects of iptakalim hydrochloride (Ipt), which is a drug reported to act as an ATP-sensitive potassium (KATP) channel opener, on selected human nAChRs heterologously expressed in the native nAChR-null SH-EP1 human epithelial cell line. Ipt reduced both peak and steadystate whole-cell current amplitudes mediated by human α4β2-nAChRs in response to nicotinic agonists. It also accelerated current decay, caused a decline in apparent efficacy of agonists, and acted in voltage- and use-dependent manners at α4β2-nAChRs. These findings and the inability of Ipt to block radiolabeled epibatidine binding to α4α2-nAChRs suggest a noncompetitive mechanism of antagonism. Other studies discount effects of Ipt on nAChR internalization or involvement of KATP channels in Ipt-induced inhibition of α4β2-nAChR function. By comparison, α7-nAChRs were less sensitive than α4β2-nAChRs to Ipt acting as an antagonist. Thus, α4β2-nAChRs are among the molecular targets of Ipt, which has utility as a tool in functional characterization and pharmacological profiling of nAChRs.
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U2 - 10.1124/jpet.105.094987
DO - 10.1124/jpet.105.094987
M3 - Article
C2 - 16223869
AN - SCOPUS:31144441305
SN - 0022-3565
VL - 316
SP - 914
EP - 925
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -