RNA editing modulates the binding of drugs and highly unsaturated fatty acids to the open pore of Kv potassium channels.
The time course of inactivation of voltage-activated potassium (Kv) channels is an important determinant of the firing rate of neurons. In many Kv channels highly unsaturated lipids as arachidonic acid, docosahexaenoic acid and anandamide can induce fast inactivation. We found that these lipids interact with hydrophobic residues lining the inner cavity of the pore. We analysed the effects of these lipids on Kv1.1 current kinetics and their competition with intracellular tetraethylammonium and Kvbeta subunits. Our data suggest that inactivation most likely represents occlusion of the permeation pathway, similar to drugs that produce 'open-channel block'. Open-channel block by drugs and lipids was strongly reduced in Kv1.1 channels whose amino acid sequence was altered by RNA editing in the pore cavity, and in Kv1.x heteromeric channels containing edited Kv1.1 subunits. We show that differential editing of Kv1.1 channels in different regions of the brain can profoundly alter the pharmacology of Kv1.x channels. Our findings provide a mechanistic understanding of lipid-induced inactivation and establish RNA editing as a mechanism to induce drug and lipid resistance in Kv channels.
Decher
Niels
N
Institut für Physiologie und Pathophysiologie, Universität Marburg, Marburg, Germany. decher@staff.uni-marburg.de
Streit
Anne K
AK
Rapedius
Markus
M
Netter
Michael F
MF
Marzian
Stefanie
S
Ehling
Petra
P
Schlichthörl
Günter
G
Craan
Tobias
T
Renigunta
Vijay
V
Köhler
Annemarie
A
Dodel
Richard C
RC
Navarro-Polanco
Ricardo A
RA
Preisig-Müller
Regina
R
Klebe
Gerhard
G
Budde
Thomas
T
Baukrowitz
Thomas
T
Daut
Jürgen
J
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001665:Binding Sites; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017393:RNA Editing; D051381:Rats; D019789:Tetraethylammonium / Q000494:pharmacology*; D014982:Xenopus laevis
D005231:Fatty Acids, Unsaturated; D024642:Potassium Channels, Voltage-Gated; D016718:Arachidonic Acid; D019789:Tetraethylammonium
J Physiol. 2007 Dec 15;585(Pt 3):699-704
17584839
J Gen Physiol. 2008 May;131(5):421-9
18411332
Neurology. 1997 Apr;48(4):817-21
9109861
Neuron. 1990 Jan;4(1):39-51
2310574
Chem Biodivers. 2007 Aug;4(8):1842-57
17712822
Mol Pharmacol. 2004 Jun;65(6):1364-74
15155830
Nat Struct Mol Biol. 2004 Oct;11(10):950-6
15361858
Neuron. 2004 Sep 2;43(5):633-45
15339646
Nat New Biol. 1973 Dec 19;246(155):193-6
4519599
J Gen Physiol. 2007 May;129(5):403-18
17438120
Mol Pharmacol. 2005 Oct;68(4):995-1005
16024663
J Biol Chem. 1998 Jan 30;273(5):2639-44
9446567
Cell Biochem Biophys. 2008;52(2):59-84
18830821
Nat Med. 2008 Sep;14(9):923-30
18776886
J Biol Chem. 2004 Jan 2;279(1):394-400
14578345
FEBS Lett. 2002 Oct 30;531(1):2-6
12401193
Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5092-5
2052588
Pharmacol Res. 2007 Nov;56(5):428-42
17933549
Science. 2004 Apr 9;304(5668):265-70
15031437
J Gen Physiol. 1971 Oct;58(4):413-37
5112659
Eur J Neurosci. 1992;4(8):708-722
12106315
Nature. 1994 May 26;369(6478):289-94
8183366
Channels (Austin). 2008 May-Jun;2(3):202-9
18836299
Neuroscientist. 2006 Jun;12(3):245-60
16684969
FEBS Lett. 1988 Dec 19;242(1):199-206
2462513
Nature. 2001 Jun 7;411(6838):657-61
11395760
Ann Neurol. 2006 Nov;60(5):586-96
17044011
EMBO J. 2008 Dec 3;27(23):3164-74
18987637
FEBS Lett. 2000 Oct 13;483(1):52-6
11033355
Q Rev Biophys. 1998 Aug;31(3):239-95
10384687
Br J Pharmacol. 2008 Sep;155(1):4-16
18552881
Annu Rev Physiol. 2004;66:477-519
14977411
J Physiol. 1971 Feb;213(1):21-30
5575340
J Physiol. 1982 Oct;331:599-635
6296372
Neuron. 1997 Sep;19(3):711-22
9331360
Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1937-41
8127910
Mol Pharmacol. 2006 Oct;70(4):1204-11
16835355
J Clin Invest. 2001 Jun;107(11):1339-45
11390413
J Biol Chem. 2003 Oct 31;278(44):43807-17
12923200
Science. 2003 Aug 8;301(5634):832-6
12907802