Abstract：
:Fluoxetine is widely used for the treatment of depression. We examined the action of fluoxetine on cloned Kv4.3 stably expressed in CHO cells using the whole-cell patch-clamp technique. Fluoxetine did not significantly produce a reduction in the peak amplitude of Kv4.3, but increased the rate of current inactivation in a concentration-dependent manner. Thus, the effect of fluoxetine on Kv4.3 was measured from the integral of the current during the depolarizing pulse. The integral of Kv4.3 was reduced by fluoxetine in a concentration-dependent manner with an IC50 of 11.8μM. Using first-order kinetics analysis, the apparent association and dissociation rate constants were 1.5μM(-1)s(-1) and 22.2s(-1), respectively, with a K(D) of 14.2μM, similar to the IC50 value calculated from the concentration-response curve. Under control conditions, the inactivation of Kv4.3 was best fit by a biexponential function. The fast and slow time constants were significantly decreased in the presence of fluoxetine. Time-to-peak and activation kinetics were significantly accelerated by fluoxetine. The block of Kv4.3 by fluoxetine became more prominent as the membrane potential became more depolarized, displaying a shallow voltage dependence (δ=0.29) in the full activation voltage range. Fluoxetine did not affect the steady-state inactivation curves, but significantly accelerated the closed-state inactivation of Kv4.3. The block of Kv4.3 by fluoxetine was use-dependent during repetitive stimulation, which explained the slowing of the recovery from inactivation of Kv4.3. Our results indicate that fluoxetine blocks Kv4.3 by preferentially interacting with the open and accelerating closed-state inactivation of the channel.
journal_name
Brain Resjournal_title
Brain researchauthors
Jeong I,Choi JS,Hahn SJdoi
10.1016/j.brainres.2013.01.028subject
Has Abstractpub_date
2013-03-15 00:00:00pages
10-8eissn
0006-8993issn
1872-6240pii
S0006-8993(13)00122-4journal_volume
1500pub_type
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