Influence of the N terminus on the biophysical properties and pharmacology of TREK1 potassium channels.
نویسندگان
چکیده
TWIK-related K(+) 1 (TREK1) potassium channels are members of the two-pore domain potassium channel family and contribute to background potassium conductances in many cell types, where their activity can be regulated by a variety of physiologic and pharmacologic mediators. Fenamates such as FFA (flufenamic acid; 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid), MFA [mefenamic acid; 2-(2,3-dimethylphenyl)aminobenzoic acid], NFA [niflumic acid; 2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid], and diclofenac [2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid] and the related experimental drug BL-1249 [(5,6,7,8-tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine] enhance the activity of TREK1 currents, and we show that BL-1249 is the most potent of these compounds. Alternative translation initiation produces a shorter, N terminus truncated form of TREK1 with a much reduced open probability and a proposed increased permeability to sodium compared with the longer form. We show that both forms of TREK1 can be activated by fenamates and that a number of mutations that affect TREK1 channel gating occlude the action of fenamates but only in the longer form of TREK1. Furthermore, fenamates produce a marked enhancement of current through the shorter, truncated form of TREK1 and reveal a K(+)-selective channel, like the long form. These results provide insight into the mechanism of TREK1 channel activation by fenamates, and, given the role of TREK1 channels in pain, they suggest a novel analgesic mechanism for these compounds.
منابع مشابه
Biophysical properties of single potassium channel in the brain mitochondrial inner membrane of male rat with Alzheimer’s disease
Introduction: Alzheimer’s disease is a progressive neurodegenerative disorder, characterized by impairment of memory and changes in behavior and personality. Recent evidence suggests that mitochondrial channels play important roles in memory disorders. Accordingly, the biophysical properties of a single potassium channel were investigated in the brain mitochondrial inner membrane of rat with...
متن کاملBiophysical and electropharmacological properties of single mitoKATP channel in rat brain mitochondrial inner membrane
Introduction: Different ATP-sensitive potassium channels have been detected in the mitochondrial inner membrane of cells. They are suggested to be involved in cell processes including cell protection. Here, we characterized the biophysical and electropharmacological properties of a KATP channel in the brain mitochondrial inner membranes. Methods: After removing and homogenizing the rat brain...
متن کاملAn evidence for a potassium channel in endoplasmic reticulum based on single channel recording in bilayer lipid membrane
Introduction Numerous studies have demonstrated the presence of potassium selective channels in membranes internal organelles. These channels are essential to a large variety of cellular processes including intracellular 2+ a signaling, protein recycling, charge neutralization and cell protection. In contrast to the sarcoplasmic reticulum + here potassium channels have been clearly ...
متن کاملThe Effects of Buthotus schach Scorpion Venom on Electrophysiological Properties of Magnocellular Neurons of Rat Supraoptic Nucleus
Potassium channels are trans-membrane proteins, which selectively transport K+ ions across cell membranes and play a key role in regulating the physiology of excitability cells and signal transduction pathways. Bothutous Schach (BS) scorpion venom consists of several polypeptides that could modulate ion channels. In this study, the effects of BS crude venom on passive and active electrophysiolo...
متن کاملThe Effects of Buthotus schach Scorpion Venom on Electrophysiological Properties of Magnocellular Neurons of Rat Supraoptic Nucleus
Potassium channels are trans-membrane proteins, which selectively transport K+ ions across cell membranes and play a key role in regulating the physiology of excitability cells and signal transduction pathways. Bothutous Schach (BS) scorpion venom consists of several polypeptides that could modulate ion channels. In this study, the effects of BS crude venom on passive and active electrophysiolo...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Molecular pharmacology
دوره 85 5 شماره
صفحات -
تاریخ انتشار 2014