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 cis-polyunsaturated omega-3 fatty acids inlcuding docosahexaenoic acid (DHA), eicosapentaenoic acid. and a-linolenic acid inhibited T-type Ca2- current (IT-Ca) with IC(50)s of 2.4, 6.1, and 14.4 muM, respectively. Inhibition of IT-Ca by DHA was partially use-dependent. In the absence of stimulation, DHA (5 muM) inhibited IT-Ca by 59.7 +/- 8.1% (n = 5). When voltage steps to -10 mV were applied at 12 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. omega-3 fatty acids also selectively altered the gating kinetics of T-type Ca2+ channels. DHA accelerated T channel recovery front inactivation by approximately 3-fold but did not affect the kinetics of T channel activation or deactivation. Arachidonic acid, an omega-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. omega-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 ire neurons and cardiac myocytes could contribute significantly to their protective actions. (C) 2004 Elsevier Inc. All rights reserved.