Fluoxetine blocks cloned neuronal A-type K+ channels Kv1.4.
The effects of fluoxetine were studied on cloned K+ channel Kv1.4 stably expressed in Chinese hamster ovary (CHO) cells using the whole-cell configuration of the patch-clamp technique. Extracellular application of various concentrations of fluoxetine inhibited the amplitude of the peak current of Kv1.4 and accelerated its inactivation time course in a concentration-dependent manner. Thus, fluoxetine decreased Kv1.4 (the integral of the outward current) in a concentration-dependent manner; the IC50 was 33.1 +/- 2.5 microM. The inhibitory effect of fluoxetine was time-dependent. The apparent association (k) and dissociation (l) rate constants measured at +40 mV were 3.5 +/- 0.7 microM-1s-1 and 132.5 +/- 13.3 s-1, respectively. The Kd (= l/k) was 37.9 microM, which was close to the value obtained from the concentration-response curve. The block produced by fluoxetine increased steeply between -30 and 0 mV, which corresponded with the voltage range for channel opening. The fluoxetine block was constant at more depolarized potentials, suggesting that the block by fluoxetine was not voltage dependent. Our data indicate that fluoxetine blocks Kv1.4 channels by preferentially binding to open state.
Choi
Bok Hee
BH
Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, Socho-gu, Seoul.
Choi
Jin-Sung
JS
Ahn
Hye Sook
HS
Kim
Myung-Jun
MJ
Rhie
Duck-Joo
DJ
Yoon
Shin-Hee
SH
Min
Do-Sik
DS
Jo
Yang-Hyeok
YH
Kim
Myung-Suk
MS
Hahn
Sang June
SJ
D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular / Q000187:drug effects / Q000379:methods; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D051665:Kv1.4 Potassium Channel; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D051381:Rats
C496979:Kcna4 protein, rat; D051665:Kv1.4 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D005473:Fluoxetine