title: Forskolin suppresses delayed-rectifier K+ currents and enhances spike frequency-dependent adaptation of sympathetic neurons.
abstract: In signal transduction research natural or synthetic molecules are commonly used to target a great variety of signaling proteins. For instance, forskolin, a diterpene activator of adenylate cyclase, has been widely used in cellular preparations to increase the intracellular cAMP level. However, it has been shown that forskolin directly inhibits some cloned K+ channels, which in excitable cells set up the resting membrane potential, the shape of action potential and regulate repetitive firing. Despite the growing evidence indicating that K+ channels are blocked by forskolin, there are no studies yet assessing the impact of this mechanism of action on neuron excitability and firing patterns. In sympathetic neurons, we find that forskolin and its derivative 1,9-Dideoxyforskolin, reversibly suppress the delayed rectifier K+ current (IKV). Besides, forskolin reduced the spike afterhyperpolarization and enhanced the spike frequency-dependent adaptation. Given that IKV is mostly generated by Kv2.1 channels, HEK-293 cells were transfected with cDNA encoding for the Kv2.1 α subunit, to characterize the mechanism of forskolin action. Both drugs reversible suppressed the Kv2.1-mediated K+ currents. Forskolin inhibited Kv2.1 currents and IKV with an IC50 of ~32 μM and ~24 µM, respectively. Besides, the drug induced an apparent current inactivation and slowed-down current deactivation. We suggest that forskolin reduces the excitability of sympathetic neurons by enhancing the spike frequency-dependent adaptation, partially through a direct block of their native Kv2.1 channels.
authors.affiliation: Departamento de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chih. 32310, México.
authors.forename: Luis I
authors.initials: LI
authors.lastname: Angel-Chavez
authors.affiliation: Departamento de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chih. 32310, México.
authors.forename: Eduardo I
authors.initials: EI
authors.lastname: Acosta-Gómez
authors.affiliation: Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, Col. 28045, México.
authors.forename: Mario
authors.initials: M
authors.lastname: Morales-Avalos
authors.affiliation: Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, Col. 28045, México.
authors.forename: Elena
authors.initials: E
authors.lastname: Castro
authors.affiliation: Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, Col. 28045, México.
authors.forename: Humberto
authors.initials: H
authors.lastname: Cruzblanca
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D051669:Shab Potassium Channels / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000473:pathology
chemical_list: D051668:Delayed Rectifier Potassium Channels; D051669:Shab Potassium Channels; D005576:Colforsin; D000242:Cyclic AMP; C047983:1,9-dideoxyforskolin