Investigation of sodium channel inhibitor binding sites based on dissociation kinetics
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1
Institute of Experimental Medicine, Hungary
Although most sodium channel inhibitor (SCI) drugs are considered to bind to the local anesthetic binding site (which is the only well characterized drug binding site of sodium channels), evidence for alternative binding sites is accumulating. Most importantly, SCI compounds are so heterogeneous chemically that it is very unlikely that a single binding site could suit all molecules. For the purpose of developing novel SCI drugs it would be essential to determine alternative binding sites, and to clarify inhibition mechanisms for different binding sites. We used an electrophysiology approach (whole cell patch clamp, using rNav1.2 channel expressing HEK cells) to investigate binding sites. We have observed that inhibition by specific SCIs differ in their recovery kinetics by several orders of magnitude. We tested if a specific slowly dissociating SCI can be displaced by applying high concentration of a rapidly dissociating SCI. Displacement could be detected by observing recovery kinetics. We found that flunarizine could not be displaced by lidocaine; therefore the binding site must be different. On the other hand we found interactions between crobenetine and fluoxetine, as well as between fluoxetine and lidocaine. Interactions may suggest either competition for the same binding sites, or an allosteric interaction between the two binding sites. Our results help to identify drug binding sites of sodium channels.
Conference:
12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009.
Presentation Type:
Poster Presentation
Topic:
Developmental neurobiology and subcortical functions
Citation:
Sas
B,
Lenkey
N,
Karoly
R,
Vizi
SE and
Mike
A
(2009). Investigation of sodium channel inhibitor binding sites based on dissociation kinetics.
Front. Syst. Neurosci.
Conference Abstract:
12th Meeting of the Hungarian Neuroscience Society.
doi: 10.3389/conf.neuro.01.2009.04.073
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Received:
02 Mar 2009;
Published Online:
02 Mar 2009.
*
Correspondence:
Balázs Sas, Institute of Experimental Medicine, Budapest, Hungary, sas@koki.hu