Modulation of native T-type calcium channels by ω-3 fatty acids

Low voltage-activated, rapidly inactivating T-type Ca2+ channels are found in a variety of cells where they regulate electrical activity and Ca2+ entry. In whole-cell patch clamp recordings from bovine adrenal zona fasciculata cells, cis-polyunsaturated ω-3 fatty acids including docosahexaenoic acid (DHA), eicosapentaenoic acid, and α-linolenic acid inhibited T-type Ca2+ current (IT-Ca) with IC50s of 2.4, 6.1, and 14.4 μM, respectively. Inhibition of IT-Ca by DHA was partially use-dependent. In the absence of stimulation, DHA (5 μM) inhibited IT-Ca by 59.7 ± 8.1% (n = 5). When voltage steps to −10 mV were applied at 12 s intervals, block increased to 80.5 ± 7.2%. Inhibition of IT-Ca by DHA was accompanied by a shift of −11.7 mV in the voltage dependence of steady-state inactivation, and a smaller −3.3 mV shift in the voltage dependence of activation. ω-3 fatty acids also selectively altered the gating kinetics of T-type Ca2+ channels. DHA accelerated T channel recovery from inactivation by approximately 3-fold, but did not affect the kinetics of T channel activation or deactivation. Arachidonic acid, an ω-6 polyunsaturated fatty acid, also inhibited T-type Ca2+ current at micromolar concentrations, while the trans polyunsaturated fatty acid linolelaidic acid was ineffective. These results identify cis polyunsaturated fatty acids as relatively potent, new T-type Ca2+ channel antagonists. ω-3 fatty acids are essential dietary components that have been shown to possess remarkable neuroprotective and cardioprotective properties that are likely mediated through suppression of electrical activity and associated Ca2+ entry. Inhibition of T-type Ca2+ channels in neurons and cardiac myocytes could contribute significantly to their protective actions.