Korean J Physiol Pharmacol.  2006 Oct;10(5):243-249.

Effect of Genistein, a Tyrosine Kinase Inhibitor, on the Cloned Rat Brain Potassium Channel Kv1.5

• Choi BH

Abstract

The effect of genistein, widely used as a specific tyrosine kinase inhibitor, on rat brain Kv1.5 channels which were stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Genistein inhibited Kv1.5 currents at +50 mV in a concentration-dependent manner, with an IC50 of 54.7+/-8.2 micrometer and a Hill coefficient of 1.1+/-0.2. Pretreatment of Kv1.5 with protein tyrosine kinase inhibitors (10 micrometer lavendustin A and 100 micrometer AG1296) and a tyrosine phosphatase inhibitor (500 micrometer sodium orthovanadate) did not block the inhibitory effect of genistein. The inhibition of Kv1.5 by genistein showed voltage-independence over the full activation voltage range positive to 0 mV. The activation (at +50 mV) kinetics was significantly delayed by genistein: time constant for an activation of 1.4+/-0.2 msec under control conditions and 10.0+/-0.5 msec in the presence of 60 micrometer genistein. Genistein also slowed the deactivation of the tail currents, resulting in a crossover phenomenon: a time constant of 11.4+/-1.3 msec and 40.0+/-4.2 msec under control conditions and in the presence of 60 micrometer genistein, respectively. Inhibition was reversed by the application of repetitive depolarizing pulses, especially during the early part of the activating pulse. These results suggest that genistein directly inhibits Kv1.5 channels, independent of phosphotyrosine-signaling pathway.

Keyword

Genistein; Tyrosine kinase inhibitor; Kv1.5; Closed channel block

MeSH Terms

Animals
Brain*
Clone Cells*
Cricetinae
Cricetulus
Female
Genistein*
Inhibitory Concentration 50
Kinetics
Ovary
Patch-Clamp Techniques
Potassium Channels*
Potassium*
Protein-Tyrosine Kinases*
Rats*
Sodium
Tyrosine*
Genistein
Potassium
Potassium Channels
Protein-Tyrosine Kinases
Sodium
Tyrosine