Block effect of capsaicin on hERG potassium currents is enhanced by S6 mutation at Y652
- PMID: 19903464
- DOI: 10.1016/j.ejphar.2009.11.009
Block effect of capsaicin on hERG potassium currents is enhanced by S6 mutation at Y652
Abstract
The objectives of this study were to investigate the inhibitory action of capsaicin on wild-type (WT) and mutation human ether-a-go-go-related gene (hERG) potassium channel currents (I(hERG)), and to determine whether mutations in the S6 region are significant for the inhibition of I(hERG) by capsaicin. The hERG channel (WT, Y652A and F656A) was expressed in Xenopus oocytes and studied using standard two-microelectrode voltage-clamp techniques. The results show that capsaicin blocks WT hERG in a concentration-dependent manner, with an IC(50) of 17.45microM and a negative shift in the steady-state inactivation curve. Characteristics of blockade were consistent with capsaicin causing components of block in both the closed and open channel states. However, mutating the Y652 residue to Ala enhances the blockade effect of capsaicin with an IC(50) of 4.11microM, whereas mutation of F656A does not significantly alter drug potency. Simultaneously, for Y652A, the steady-state activation parameter is shifted to a more positive value by 5mV and the inactivation parameter is shifted to a more negative value by -29mV in the presence of 25microM capsaicin. In conclusion, capsaicin blocks hERG channels by binding to both the closed and open channel states.Y652 was important as a molecular determinant of blockade. Mutation Y652A enhances the drug block, which may cause some patients to be particularly sensitive to capsaicin clinically.
Similar articles
-
Verapamil blocks HERG channel by the helix residue Y652 and F656 in the S6 transmembrane domain.Acta Pharmacol Sin. 2007 Jul;28(7):959-67. doi: 10.1111/j.1745-7254.2007.00562.x. Acta Pharmacol Sin. 2007. PMID: 17588331
-
Blockade of the human ether-a-go-go-related gene potassium channel by ketamine.J Pharm Pharmacol. 2013 Sep;65(9):1321-8. doi: 10.1111/jphp.12095. Epub 2013 Jul 10. J Pharm Pharmacol. 2013. PMID: 23927470
-
Block of hERG channel by ziprasidone: biophysical properties and molecular determinants.Biochem Pharmacol. 2006 Jan 12;71(3):278-86. doi: 10.1016/j.bcp.2005.10.047. Epub 2005 Dec 1. Biochem Pharmacol. 2006. PMID: 16325148
-
Blockade of the human ether-a-go-go-related gene potassium channel by ketanserin.Sheng Li Xue Bao. 2008 Aug 25;60(4):525-34. Sheng Li Xue Bao. 2008. PMID: 18690396
-
Inhibition of HERG channels by the local anaesthetic articaine.Eur J Anaesthesiol. 2007 Feb;24(2):148-53. doi: 10.1017/S0265021506001311. Epub 2006 Aug 29. Eur J Anaesthesiol. 2007. PMID: 16938156
Cited by
-
A Statistical Thermodynamic Model for Ligands Interacting With Ion Channels: Theoretical Model and Experimental Validation of the KCNQ2 Channel.Front Pharmacol. 2018 Mar 9;9:150. doi: 10.3389/fphar.2018.00150. eCollection 2018. Front Pharmacol. 2018. PMID: 29593528 Free PMC article.
-
HPLC-based activity profiling for pharmacologically and toxicologically relevant natural products - principles and recent examples.Pharm Biol. 2019 Dec;57(1):328-334. doi: 10.1080/13880209.2019.1606261. Pharm Biol. 2019. PMID: 31057026 Free PMC article. Review.
-
Definition of fatty acid transport protein-2 (FATP2) structure facilitates identification of small molecule inhibitors for the treatment of diabetic complications.Int J Biol Macromol. 2023 Jul 31;244:125328. doi: 10.1016/j.ijbiomac.2023.125328. Epub 2023 Jun 10. Int J Biol Macromol. 2023. PMID: 37307967 Free PMC article.
-
Capsaicin inhibits the spontaneous pacemaker activity in interstitial cells of cajal from the small intestine of mouse.J Neurogastroenterol Motil. 2010 Jul;16(3):265-73. doi: 10.5056/jnm.2010.16.3.265. Epub 2010 Jul 27. J Neurogastroenterol Motil. 2010. PMID: 20680165 Free PMC article.
-
Capsaicin Inhibits Multiple Voltage-Gated Ion Channels in Rabbit Ventricular Cardiomyocytes in TRPV1-Independent Manner.Pharmaceuticals (Basel). 2022 Sep 26;15(10):1187. doi: 10.3390/ph15101187. Pharmaceuticals (Basel). 2022. PMID: 36297299 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources