Implication in the regulation of the vascular tone
T-type calcium channels (T-channels) are important actors in neuronal pacemaking, in heart rhythm, and in the control of the vascular tone. T-channels are regulated by several endogenous lipids including the primary eicosanoid arachidonic acid (AA), which display an important role in vasodilation via its metabolism leading to prostanoids, leukotrienes, and epoxyeicosatrienoic acids (EETs). However, the effects of these latter molecules on T-currents have not been investigated. Here, we describe the effects of the major cyclooxygenase, lipoxygenase, and cytochrome P450 epoxygenase products on the three human recombinant T-channels (Ca(v)3.1, Ca(v)3.2, and Ca(v)3.3), as compared to those of AA. We identified the P450 epoxygenase product, 5,6-EET, as a potent physiological inhibitor of Ca(v)3 currents. The effects of 5,6-EET were observed at sub-micromolar concentrations (IC50 = 0.54 mu M), occurred in the minute range, and were reversible. The 5,6-EET inhibited the Ca(v)3 currents at physiological resting membrane potentials mostly by inducing a large negative shift in their steady-state inactivation properties. Using knockout mice for Ca(v)3.1 and Ca(v)3.2, we demonstrated that the vasodilation of preconstricted mesenteric arteries induced by 5,6-EET was specifically impaired in Ca(v)3.2 knockout mice. Overall, our results indicate that inhibition of Ca(v)3 currents by 5,6-EET is an important mechanism controlling the vascular tone.
Pfluegers Archiv, 2014, Vol 466, Issue 9, p. 1759-1768