Electrostatic Tuning of Cellular Excitability

Abstract

Voltage-gated ion channels regulate the electric activity of excitable tissues, such as the heart and brain. Therefore, treatment for conditions of disturbed excitability is often based on drugs that target ion channels. In this study of a voltage-gated K channel, we propose what we believe to be a novel pharmacological mechanism for how to regulate channel activity. Charged lipophilic substances can tune channel opening, and consequently excitability, by an electrostatic interaction with the channel's voltage sensors. The direction of the effect depends on the charge of the substance. This was shown by three compounds sharing an arachidonyl backbone but bearing different charge: arachidonic acid, methyl arachidonate, and arachidonyl amine. Computer simulations of membrane excitability showed that small changes in the voltage dependence of Na and K channels have prominent impact on excitability and the tendency for repetitive firing. For instance, a shift in the voltage dependence of a K channel with -5 or +5 mV corresponds to a threefold increase or decrease in K channel density, respectively. We suggest that electrostatic tuning of ion channel activity constitutes a novel and powerful pharmacological approach with which to affect cellular excitability.

Tetraphenylporphyrin derivative specifically blocks members of the voltage-gated potassium channel subfamily Kv1

“…Alternatively, negatively charged amphiphiles, for example, free polyunsaturated fatty acids (PUFAs) can potentially bind to the voltage sensor, modulating the voltage-dependence of Kv channel activation. 10,31 Furthermore, binding of por3 to phospholipid may be attenuated at positive potentials because of its positive charges. This property could well explain the voltage-dependence of Kv channel block by por3.…”

“…The drug effect on voltage-sensor movement may involve a direct targeting of the voltage-sensor or an indirect effect, due to an alteration of the lipid surrounding. [7][8][9][10] Tetraphenylporphyrin derivatives have been developed as a new class of synthetic ligands for potassium channels. 11 These water-soluble ligands have 4-fold symmetry and were designed to interact simultaneously with all 4 subunits of the tetrameric Kv channel to mimic the action of toxins that target the extracellular entrance of the Kv channel pore.…”

Intracellular K+ Concentration Decrease Is Not Obligatory for Apoptosis

“…laevis oocytes were dissected and stored as described previously (7,8) For combined electrophysiological and K ϩ -selective microelectrode measurements on the same cell, oocytes expressing cloned voltage-gated K (Kv) 3 channels were used. cRNAs for the Shaker Kv channel with fast inactivation removed and for the R365C and W434F mutants were injected as described previously (8), and cRNA-injected cells were incubated for 3-6 days at 11°C in an antibiotic-supplemented modified Barth's solution (7,8) before measurements. 2 .…”

“…The 100K solution was added continuously to the bath using a gravitydriven perfusion system. Two-electrode voltage clamp measurements of K ϩ currents were performed as described previously (8). The holding potential was set to Ϫ80 mV and currents achieved by stepping to potentials between Ϫ80 and ϩ50 mV for 100 ms in 5-mV increments.…”

Functionalized ZnO nanorod-based selective magnesium ion sensor for intracellular measurements

“…Stage III and VI oocytes (approximately 1 mm in diameter) without spots and with clear delimitation between the animal and vegetal pole were selected. All details regarding preparation of oocytes and the solutions used are described in (Börjesson et al, 2010).…”