Potent block of potassium channels by MEK inhibitor U0126 in primary cultures and brain slices
Year: 2018
Type: article
Abstract: U0126 (1,4-diamino-2,3-dicyano-1,4-bis (2-aminophenylthio) butadiene), a widely used mitogen-activated protein kinase kinase (MEK) inhibitor, was found to accelerate voltage-gated K+channel (KV) inactivation in heterologous cells expressing several types of KV. The goal of this study was to examine whether U0126 at a concentration thought to specifically inhibit MEK signaling also inhibits KVin native neurons of primary cultures or brain slices. U0126 caused a dose-dependent inhibition of both the transient (IA) and sustained (IDR) components of K+currents in hippocampal neurons. U0126 also exhibited much higher potency on the IAand IDRthan the classical KVblockers 4-aminopyridine (4-AP) and tetraethylammonium (TEA). Consistent with its inhibitory effect on KV, U0126 broadened action potential duration, profoundly affected the repolarizing phase, and dramatically reduced firing frequency in response to current pulse injections. Despite the potent and reversible action of U0126 on Kvchannels, PD98059, a structurally-unrelated MEK inhibitor, did not induce such an effect, suggesting U0126 may act independently of MEK inhibition. Together, these results raise cautions for using U0126 as a specific inhibitor for studying MEK signaling in neurons; on the other hand, further studies on the blocking mechanisms of U0126 as a potent inhibitor of KVmay provide useful insights into the structure-function relationship of KVin general.
Source: Scientific Reports
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Award: G8626570189
OpenAlex ID: W2806568015