Modulation of T-type calcium channels by bioactive lipids

Abstract

T-type calcium channels (T-channels/CaV3) have unique biophysical properties allowing a calcium influx at resting membrane potential of most cells. T-channels are ubiquitously expressed in many tissues and contribute to low-threshold spikes and burst firing in central neurons as well as to pacemaker activities in cardiac cells. They also emerged as potential targets to treat cancer and hypertension. Regulation of these channels appears complex, and several studies have indicated that CaV3.1, CaV3.2, and CaV3.3 currents are directly inhibited by multiple endogenous lipids independently of membrane receptors or intracellular pathways. These bioactive lipids include arachidonic acid and ω3 poly-unsaturated fatty acids; the endocannabinoid anandamide and other N-acylethanolamides; the lipoamino-acids and lipo-neurotransmitters; the P450 epoxygenase metabolite 5,6-epoxyeicosatrienoic acid; as well as similar molecules with 18-22 carbons in the alkyl chain. In this review, we summarize evidence for direct effects of these signaling molecules, the molecular mechanisms underlying the current inhibition, and the involved chemical features. The impact of this modulation in physiology and pathophysiology is discussed with a special emphasis on pain aspects and vasodilation. Overall, these data clearly indicate that T-current inhibition is an important mechanism by which bioactive lipids mediate their physiological functions.

Leukotriene B4 Inhibits L-Type Calcium Channels via p38 Signaling Pathway in Vascular Smooth Muscle Cells

“…AA and its metabolites have been shown to directly inhibit T-type calcium channels [1]. AA has also been shown to inhibit L-type calcium channels in a direct way [3].…”

Endocannabinoid signalling and the deteriorating brain

“…Striking examples are T-type Ca 2+ channels (particularly Ca v 3.2 and Ca v 3.3), which are involved in the establishment of associative long-term potentiation, and whose levels wane with ageing 121 . These channels are blocked by physiological concentrations of N -arachidonoyldopamine and N -arachidonoylserotonin, which exhibit nanomolar affinity in binding assays and are therefore among their strongest endogenous inhibitors 122 . Thus, if the levels of these eCB-like mediators were to be enhanced or reduced following pharmacological inhibition of FAAH, this could impact upon synaptic plasticity and potentially result in memory disturbances.…”

Non‐endocannabinoid N‐acylethanolamines and 2‐monoacylglycerols in the intestine

“…TRPV1 can be activated by several NAEs and monoacylglycerols (Movahed et al, ; Iwasaki et al, ); a possible involvement of this receptor in the anorectic effects of NAEs and 2‐MAGs will be discussed below. NAEs have been reported to inhibit a number of ion channels, that is, OEA can inhibit voltage‐gated Na + ‐channels , low‐voltage‐activated (T‐type, Ca v 3.x) channels and high‐voltage‐activated dihydropyridine‐sensitive (L‐type Ca v 1.x)‐channels as well as the K + ‐channels K v 3.4 and K v 1.5 (Amoros et al, ; Barana et al, ; Voitychuk et al, ; Chemin et al, ). It is unclear whether these in vitro effects have any physiological or pharmacological significance in the intestine in vivo .…”