Electrostatic tuning of cellular excitability.
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.
Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, Linköping, Sweden.
Sara I
SI
Börjesson
Teija
T
Parkkari
Sven
S
Hammarström
Fredrik
F
Elinder
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000465:Algorithms; D000818:Animals; D016718:Arachidonic Acid / Q000737:chemistry / Q000494:pharmacology; D001095:Arachidonic Acids / Q000737:chemistry / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003198:Computer Simulation; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051637:Shaker Superfamily of Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity; D014982:Xenopus laevis
D001095:Arachidonic Acids; D051637:Shaker Superfamily of Potassium Channels; D015222:Sodium Channels; D016718:Arachidonic Acid