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.
Highlights
IntroductionA plethora of natural or synthetic molecules have been currently used as pharmacological tools to search for the nature of intracellular pathways that underlies
In signal transduction research, a plethora of natural or synthetic molecules have been currently used as pharmacological tools to search for the nature of intracellular pathways that underliesPLOS ONE | DOI:10.1371/journal.pone.0126365 May 11, 2015Forskolin Reduces Neuronal Excitability specific cellular processes [1]
To assess if the cAMP pathway underlies the enhancement of IKV, cells were transiently exposed to 20 μM FSK
Summary
A plethora of natural or synthetic molecules have been currently used as pharmacological tools to search for the nature of intracellular pathways that underlies. Forskolin Reduces Neuronal Excitability specific cellular processes [1]. For instance forskolin (FSK), an activator of adenylate cyclase, is frequently applied to cellular preparations to study cAMP-dependent transduction pathways [2,3,4,5]. Early evidence shows that FSK may have cAMP-independent effects on ligand- or voltage-gated ion currents [6,7,8]. Voltage-gated K+ channels generate the resting membrane potential, shape the action potential and regulate the firing pattern [12,13]. There are no studies in excitable cells exploring the effect on repetitive firing of the FSK-mediated K+ channel block
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