5,6-EET potently inhibits T-type calcium channels: implication in the regulation of the vascular tone

Abstract

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 (Cav3.1, Cav3.2, and Cav3.3), as compared to those of AA. We identified the P450 epoxygenase product, 5,6-EET, as a potent physiological inhibitor of Cav3 currents. The effects of 5,6-EET were observed at sub-micromolar concentrations (IC50 = 0.54 μM), occurred in the minute range, and were reversible. The 5,6-EET inhibited the Cav3 currents at physiological resting membrane potentials mostly by inducing a large negative shift in their steady-state inactivation properties. Using knockout mice for Cav3.1 and Cav3.2, we demonstrated that the vasodilation of preconstricted mesenteric arteries induced by 5,6-EET was specifically impaired in Cav3.2 knockout mice. Overall, our results indicate that inhibition of Cav3 currents by 5,6-EET is an important mechanism controlling the vascular tone.

T-type calcium channels are involved in hypoxic pulmonary hypertension

“…12 However, Ca v 3.2 VGCC may play a complex role since it is implicated in vascular relaxation in the coronary artery 21 or it can antagonize relaxation elicited by 5,6-EETs (epoxyeicosatrienoic acids). 37 While the role of L-VGCC in IPA contraction has been extensively described, 38 concentrations used in the present experiments are far greater and this does not allow to discriminate between the respective involvement of Ca v 3.1 and Ca v 3.2 isotypes in the contraction. NNC550396 is a less selective inhibitor of T-VGCC since it inhibits T-and L-VGCC as previously described .…”

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

“…The actions of the EETs are perhaps the best studied because these epoxides are reported to modulate cardiac function via cardiac L-type Ca 2+ currents (Xiao et al, 2004), K ATP currents , and even T-type Ca 2+ currents (Cazade et al, 2013)-observations that fit well with the smaller QT prolongation and the less marked ST elevation in isolated murine hearts after perfusion with 14,15-EET . Like many other actions of the EETs, the positive effects on cardiac myocytes reportedly relied on the activation of PKA.…”

Regulation of CYP2J2 and EET Levels in Cardiac Disease and Diabetes

“…The heart’s electrophysiology is governed by various ion channels. While there is an abundance of studies demonstrating the effect of EETs on several ion channels in the heart, fewer studies have demonstrated specifically that CYP2J2 levels can affect cardiac electrophysiology [ 95 , 96 , 97 , 98 , 99 , 100 ]. One study by Lu et al found that when CYP2J2 is overexpressed in transgenic mouse hearts, basal K ATP currents were almost two-fold greater when compared with wild-type mice [ 101 ].…”