title: Effects of lobeline, a nicotinic receptor ligand, on the cloned Kv1.5.
abstract: The goal of the present study was to examine the effects of lobeline, an agonist at nicotinic receptors, on cloned Kv channels, Kv1.5, Kv3.1, Kv4.3, and human ether-a-gogo-related gene (HERG), which are stably expressed in Chinese hamster ovary (CHO) or human embryonic kidney 293 (HEK293) cells. Whole-cell patch-clamp experiments revealed that lobeline accelerated the decay rate of Kv1.5 inactivation, decreasing the current amplitude at the end of the pulse in a concentration-dependent manner with a half-maximal inhibitory concentration (IC(50)) value of 15.1 μM. Using a time constant for the time course of drug-channel interaction, the apparent association (k(+1)), and dissociation rate (k(-1)) constants were 2.4 μΜ(-1) s(-1) and 40.9 s(-1), respectively. The calculated K(D) was 17.0 μΜ. Lobeline slowed the decay rate of the tail current, resulting in a tail crossover phenomenon. The inhibition of Kv1.5 by lobeline steeply increased at potentials between -10 and +10 mV, which corresponds to the voltage range of channel activation. At more depolarized potentials a weaker voltage dependence was observed (δ=0.26). The voltage dependence of the steady-state activation curve was not affected by lobeline, but lobeline shifted the steady-state inactivation curve of Kv1.5 in the hyperpolarizing direction. Lobeline produced use-dependent inhibition of Kv1.5 at frequencies of 1 and 2 Hz, and slowed the recovery from inactivation. Lobeline also inhibited Kv3.1, Kv4.3, and HERG in a concentration-dependent manner, with IC(50) values of 21.7, 28.2, and 0.34 μM, respectively. These results indicate that lobeline produces a concentration-, time-, voltage-, and use-dependent inhibition of Kv1.5, which can be interpreted as an open-channel block mechanism.
authors: Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul, 137-701, South Korea.
authors: Imju
authors: I
authors: Jeong
authors: Bok Hee
authors: BH
authors: Choi
authors: Sang June
authors: SJ
authors: Hahn
mesh_terms: D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors / Q000187:drug effects*; D008120:Lobeline / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors; D051670:Shaw Potassium Channels / Q000037:antagonists & inhibitors; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; C489597:KCNC1 protein, human; D051666:Kv1.5 Potassium Channel; D051672:Shal Potassium Channels; D051670:Shaw Potassium Channels; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D008120:Lobeline