External blockade of the major cardiacdelayed-rectifier K+ channel (Kv1.5) by polyunsaturated fattyacids.

Abstract

The present work shows that arachidonic acid and some other long chain polyunsaturated fatty acids such as docosahexaenoic acid, which is abundant in fish oil, produce a direct open channel block of the major voltagedependent K+ channel (Kv1.5) cloned in cardiac cells. The inhibitory action of these selected fatty acids is seen when they are applied extracellularly but not when they are included in the patch pipette. Fatty acids then appear to bind to an external site on the Kv1.5 channel structure. Inhibition of Kv1.5 channel activity by polyunsaturated fatty acids (acceleration of the apparent inactivation and decrease of the peak current) is similar to that produced by the class m antiarrhythmic tedisamil. Docosahexaenoic acid and arachidonic acid also inhibit the delayed-rectifier K+ channel currents in cultured mouse and rat cardiomyocytes. These results are discussed in the light of the reported fatty acids effects on cardiac function in disasd states. Since Kv1.5 is also present in the brain, the results reported here could also have a significance in terms of processes such as long-term potentiation or depression.Fatty acids play an important role in the life and death of cardiac cells because (i) they are essential fuels for mechanical, electrical, and synthetic activities of the heart; (ii) their level is abnormally high in an ischemia followed by a reperfusion; and (iii) dietary fish oil is apparently beneficial for heart function (for a review, see ref. 1).In heart, voltage-gated K+ channels determine the resting potential, shape, and length of the action potential, thus controlling cardiac performance. Several different types of voltage-sensitive K+ channels are expressed in myocytes (for reviews, see refs. 2 and 3), and their intrinsic properties are regulated by guanine nucleotide-binding proteins (4) and by different types of kinases (5). Activation of one class of cardiac K+ channels by intracellular arachidonic acid (AA) has also been observed (6-8).

Arachidonic Acid Inhibits Transient Potassium Currents and Broadens Action Potentials during Electrographic Seizures in Hippocampal Pyramidal and Inhibitory Interneurons

“…Recently, however, A A has been shown to inhibit currents directly through channels formed by members of the Kv4 (Shal ) subfamily of voltage-dependent potassium channels, whereas other members of Shaker subfamilies were relatively insensitive to A A (Villaroel and Schwarz, 1996; however, see Honore et al, 1994). Kv4.2 protein is strongly expressed across the somatodendritic axis of hippocampal CA1 pyramidal neurons (Sheng et al, 1992;Maletic-Savatic et al, 1995), and recent evidence suggests that the predominant A-type transient current throughout principal neurons of the CNS arises from channels formed by Kv4.2 (Serodio et al, 1994).…”

Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons.

“…Outward potassium currents are also inhibited in cardiac cells (ref. 5; Y. F. Xiao, J. P. Morgan, and A.L., unpublished data) and in pinealocytes (6). The net physiologic effect of the PUFAs on the heart is to stabilize the myocytes electrically (7,8), resulting in an antiarrhythmic action (9).…”

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

“…One such group of candidate substances is the polyunsaturated fatty acids (PUFAs) with a highly lipophilic acyl tail with two or more double bonds and a negatively charged carboxyl head group. PUFAs have been shown to shift the voltage-dependence of activation and/or inactivation of a number of different voltagegated ion channels [123][124][125][126][127][128] suggesting a general and relatively unspecific mechanism of action. Direct PUFA-binding to the channel protein as well as PUFA-induced changes in the properties of the membrane have been suggested.…”