Cocaine inhibits cromakalim-activated K+ currents in follicle-enclosed Xenopus oocytes.
The effect of cocaine on K+ currents activated by the KATP channel opener cromakalim was investigated in follicular cells of Xenopus oocytes. The results indicate that cocaine in the concentration range of 3-500 microM reversibly inhibits cromakalim-induced K+ currents. The IC50 value for cocaine was 96 microM. Inhibition of the cromakalim-activated K+ current by cocaine was noncompetitive and voltage independent. Pretreatment with the Ca2+ chelator BAPTA did not modify the cocaine-induced inhibition of cromakalim-induced K+ currents, suggesting that Ca2+-activated second messenger pathways are not involved in the actions of cocaine. Outward K+ currents activated by the application of 8-Br-cAMP or forskolin were also inhibited by cocaine. The EC50 and slope values for the activation of K+ currents by cromakalim were 184+/-19 microM and 1.14 in the absence of cocaine as compared to 191+/-23 microM and 1.03 in the presence of cocaine (300 microM). Cocaine also blocked K+ currents mediated through C-terminally deleted form of Kir6.2 (KirDeltaC26) in the absence of sulfonylurea receptor with an IC50 value of 87 microM, suggesting that cocaine interacts directly with the channel forming Kir6.2 subunit. Radioligand binding studies indicated that cocaine (100 microM) did not affect the binding characteristics of the KATP ligand, [3H]glibenclamide. These results demonstrate that cromakalim-activated K+ currents in follicular cells of Xenopus oocytes are modulated by cocaine.
Oz
Murat
M
Cellular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland 21224, USA. moz@intra.nida.nih.gov
Zakharova
Irina
I
Dinc
Meral
M
Shippenberg
Toni
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019806:Cromakalim / Q000494:pharmacology*; D005260:Female; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006080:Ovarian Follicle / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology*; D011869:Radioligand Assay; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014982:Xenopus laevis
D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D019806:Cromakalim; D000255:Adenosine Triphosphate; D003042:Cocaine