Pflugers Arch - Eur J Physiol (2014) 466:689–700 DOI 10.1007/s00424-014-1467-5

INVITED REVIEW

Modulation of T-type calcium channels by bioactive lipids Jean Chemin & Magali Cazade & Philippe Lory

Received: 26 December 2013 / Revised: 24 January 2014 / Accepted: 29 January 2014 / Published online: 16 February 2014 # Springer-Verlag Berlin Heidelberg 2014

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 This article is published as a part of the Special Issue on T-type calcium channels. J. Chemin (*) : M. Cazade : P. Lory Institut de Génomique Fonctionnelle, Universités Montpellier 1 & 2, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5203, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France e-mail: [email protected] J. Chemin : M. Cazade : P. Lory INSERM U661, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France J. Chemin : M. Cazade : P. Lory LabEx Ion Channel Science and Therapeutics, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France

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. Keywords Analgesia . Knock-out . Mesenteric . N-arachidonoyl glycine . TTA-A2 . Vascular tone

Introduction Voltage-dependent calcium (Ca2+) channels (VDCCs/CaV) are divided into three families: the L-type Ca2+ channels (CaV1 family), the neuronal N-, P/Q-, and R-type Ca2+ channels (CaV2 family), and the T-type Ca2+ channels (CaV3 family). T-type Ca2+ channels (T-channels) are specifically activated by small membrane depolarization producing a Ca2+ entry near the cell membrane resting potential. The electrophysiological features of T-channels are low voltageactivated Ca2+ currents, low unitary conductance, fast inactivation and slow deactivation kinetics, and strong steady-state inactivation at physiological resting potentials [69, 86]. Three T-channel subunits have been identified, CaV3.1 (or α1G), CaV3.2 (or α1H), and CaV3.3 (or α1I), which display specific properties. CaV3.1 and CaV3.2 are widely expressed in various tissues in particular in the nervous system and cardiovascular tissues and display typical properties of native T-channels (including fast inactivation kinetics), whereas CaV3.3 is restricted to the central nervous system, particularly in the reticular neurons of the thalamus, where it displays Tcurrents with unusually slow inactivation kinetics [69, 86]. In the nervous system, T-channels are implicated principally in spontaneous firing, sleep, epilepsy, and pain perception [52, 57, 69, 89]. In the cardiovascular system, T-channels are involved in the cardiac pacemaker and in the vasoconstriction as well as in pathophysiological states such as cardiac

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hypertrophy and hypertension [48, 57, 65, 69]. T-channels are also involved in the proliferation and the differentiation of several tissues and emerged as a pharmacological target for the treatment of cancer [53, 67]. In contrast with the regulation of Ca2+ channels of the CaV1 and the CaV2 families, the pathways regulating the activity of T-channels emerged only recently and their modulation by hormones and neurotransmitters depend on the cell type studied and/or the recording conditions [19, 40]. Moreover, Tchannels are modulated independently of G protein-coupled receptors and protein kinases by several endogenous compounds including redox agents [90] and bioactive lipids including fatty acids, endocannabinoids, lipoamino-acids, and arachidonic acid metabolites. In this review, we summarize evidence for the direct effects of these bioactive lipids on Tcurrents and discuss the relevance of these modulations in neuronal and cardiovascular physiology.

Fatty acids The most studied fatty acid is arachidonic acid (AA) because it is the precursor of prostaglandins, leukotrienes, and epoxyeicosatrienoic acids (EETs), which display important function in inflammation and in the regulation of the vascular tone [12, 42, 76, 105]. AA is a 20-carbon omega 6 polyunsaturated fatty acid with four cis-double bonds (20:4 ω6), which is liberated from membrane phospholipids by phospholipases of the class A2 that are usually activated by Gq proteincoupled receptors [72]. Several studies have demonstrated that AA inhibits Ttype Ca2+ current including native T-currents in bovine adrenal zona fasciculate cells [25], osteoblast cells [22], NG108-15 cells [80], and currents from recombinant CaV3.1, CaV3.2, and CaV3.3 channels (Fig. 1) [18, 87, 106]. Importantly, T-currents are inhibited by micromolar concentrations of AA (EC50 =3.9 μM for CaV3.1 current [87]), which are in the physiological range and below the critical micelle concentration, at which AA could exert detergent effect [59, 60]. The effect of AA occurs in the minute range and is reversible upon perfusion of bovine albumin serum (BSA) (Fig. 1a) [18, 25, 87]. The potency of AA on the three recombinant CaV3 currents is CaV3.2 > CaV3.1 > CaV3.3 [18]. The effect of AA is independent of its metabolism and persists during pharmacological block of cyclo-oxygenase (COX), lipo-oxygenase (LOX), and P450 epoxygenase (but see below). In addition, the effect of AA is observed in cellfree inside-out patches using an intracellular medium lacking both GTP and ATP indicating that AA acts directly on Tcurrents or via their near membrane environment (Fig. 1b) [18, 87] (but see also [106]). At the single channel level, AA increases the number of blank sweeps (without activity) but

Pflugers Arch - Eur J Physiol (2014) 466:689–700

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Fig. 1 Inhibition of T-current by arachidonic acid. a Inhibition of CaV3.1 current recorded in the whole-cell mode by arachidonic acid (AA) and current recovery after washout with a bovine serum albumin (BSA) solution. b Similar experiments in the cell-free inside-out configuration. c Effects of 3 μM AA (white circles) on the activation and the steady-state inactivation curves of CaV3.1 current. a and (c) adapted from reference [87] and (b) from reference [18]

not affects the single channel conductance [87]. At the macroscopic level, AA accelerates the inactivation kinetics of Tcurrent and shifts their steady-state inactivation properties toward negative potentials leading to T-current inhibition at physiological resting potentials (below −80 mV) (Fig. 1c) [18, 25, 87, 106]. In contrast, AA has minor effect on the steadystate activation curve but induces a significant negative shift in the foot of the activation curve (Fig. 1c) [18, 25, 87, 106]. Modeling experiments demonstrated that AA acts on Tchannels that are either in inactivated state or in intermediate closed states and stabilizes the channels in one or the other conformation [87]. Interestingly, using mutagenesis, it was demonstrated that CaV3.1 mutants that present slower inactivation kinetics than WT channels show an increased affinity for AA and are consequently inhibited more rapidly with a ∼10-fold lower IC50 [87]. These results indicate that the structural determinants of fast inactivation are involved in the AA–channel interaction. In addition to AA, several other poly-unsaturated fatty acids inhibit T-currents (Fig. 2) [18, 25]. The T-current inhibition mainly depends on the degree of unsaturation of the alkyl chain (but not on the chain length) and increases with the number of cis-double bonds (Fig. 2b) [18]. The inhibition of T-currents is not restricted to eicosanoids (20 carbons) and occurs with fatty acids containing 18–22 carbons (Fig. 2a). The T-current inhibition is also increased for poly-unsaturated

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Fig. 2 Effect of several fatty acids on T-current: Importance of the double bond number. a Schematic chemical structure and inhibitory effect on CaV3.3 current of palmitic acid (16:0), palmitoleic acid (16:1), linoleic acid (18:2), stearidonic acid (18:4), eicosapentaenoic acid (20:5, EPA), and docosahexaenoic acid (22:6, DHA). b Inhibition of CaV3.2 current by fatty acids containing 18 (C18), 20 (C20), and 22 carbons (C22) presented as function of the double bond number. Adapted from reference [18]

fatty acids when cis-double bonds are close to the carboxyl group [18]. By contrast, fatty acids in trans-configuration or containing cis-triple bonds (as linolenelaidic acid and ETYA, respectively) have negligible effects [18]. Overall, these data indicate that the major natural and endogenous fatty acids, including α-linolenic acid (18:3 ω6), mead acid (20:3 ω9), and arachidonic acid (20:4 ω6), as well as the fully polyunsaturated ω3 fatty acids stearidonic acid ( 1 8 : 4 ) , e i c o s a p e n t a e n o i c a c i d ( 2 0 : 5 , E PA ) , a n d docosahexaenoic acid (22:6, DHA), which are supplied by alimentation and enriched in fish oil, are potent inhibitors of T-currents (Fig. 2a) [18, 25]. Considering the role of polyunsaturated ω3 fatty acids in both cardiovascular diseases and neuronal function [4, 20, 50, 51, 70, 98], it is attractive to suggest that the T-channel inhibition may contribute to their beneficial effects, but future studies are necessary to clarify this issue.

The endocannabinoid anandamide The first identified endogenous cannabinoid (CB) receptor agonist, N-arachidonoylethanolamide (NAEA), was given the name, anandamide, which is derived from the Indian Sanskrit term ananda for bliss [26]. Anandamide is a small lipid molecule that resembles no known neurotransmitter but shares structural features with eicosanoids. Indeed, anandamide structure consists of arachidonic acid associated with an ethanolamine. Anandamide is produced by a two-step process which required intracellular calcium [71]. The N-acyltransferase catalyzes first the formation of the anandamide precursor N-arachidonoyl-phosphatidylethanolamine (NAPE) from phosphatidylethanolamine (PE) and arachidonic acid, which is followed by the cleavage of NAPE, catalyzed by an uncharacterized phospholipase D that produces anandamide and phosphatidic acid [71]. Anandamide binds to and activates CB1 receptors to mediate physiological and behavioral effects similar to those of Δ9-tetrahydrocannabinol (THC; the main psychoactive component of marijuana), including hypothermia, hypokinesia, analgesia, and catalepsy [2, 27, 58]. However, several pharmacological effects of anandamide are independent of CB1 receptors, including modulation of neuronal excitability [92, 99], pain [1, 101], and cardiovascular function [43, 49]. Interestingly, anandamide was also isolated from rat brain and shown to bind to L-type Ca2+ channels at the 1,4dihydropyridine site [45, 83]. This finding did not receive much attention, and its functional implications are not clear as yet. Nevertheless, it already indicated that anandamide is not selective for the cannabinoid receptors and that its neuromodulatory actions might be more complex than originally thought. In fact, anandamide modulates the activity of several ion channels [66, 96], including T-type Ca2+ channels, which could contribute to its pharmacological effects. Anandamide inhibits recombinant CaV3 currents expressed in HEK-293, COS, and CHO cells. Micromolar concentration of anandamide inhibits T-currents at every potential with different potency among CaV3 isoforms: IC50 values were 0.3 μM for CaV3.2, 1.1 μM for CaV3.3, and 4.1 μM for CaV3.1 [15]. Anandamide inhibits T-currents independently of CB receptors and G proteins, and this effect is not observed with the synthetic cannabinoids WIN 55,212-2 and CP 55,490, but the CB1 antagonist SR141716A (trade name Acomplia, commercialized to treat obesity) was a potent blocker inducing ∼70 % inhibition at 1 μM [15]. Also, anandamide effect persists in cell-free inside-out patches suggesting that anandamide acts directly at the CaV3 protein or via its near membrane environment. The metabolism of anandamide, including AA formation catalyzed by the fatty acid amide hydrolase (FAAH, the main enzymemetabolizing NAEA), is not involved in anandamide effects since the non-hydrolyzable anandamide analogs

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that endocannabinoids could modulate neuronal development by direct inhibition of T-currents [16]. A structure–function study has demonstrated that both the alkyl chain of anandamide and the hydroxyl present in its head group are primarily responsible for T-current inhibition (Fig. 3) [18]. Anandamide derivatives lacking the hydroxyl group are weak inhibitors of T-currents (arachidonamide, arachidonic acid N-methyl amide (ANMA), and arachidonyl 2′-chloroethylamide (ACEA), Fig. 3). The amide linkage also contributes to increase anandamide effects since arachidonic acid (that contains a carboxyl group and the same alkyl chain as anandamide but not the amide linkage) inhibits T-currents to a lesser extent than anandamide. Thus, arachidonic acid methyl ester, which lacks both the reactive hydroxyl group and the amide linkage, has negligible on T-currents (Fig. 3). It should be noted that arachidonic alcohol has the same potency as arachidonic acid suggesting that the carbonyl group is not crucial for anandamide effects. Overall, these results suggest that anandamide and fatty acids could act on T-channels primarily using their –OH group, presumably via hydrogen bonds (Fig. 3) [18].

R1- and R2-methanandamide produce similar or even greater inhibition (Fig. 3) [15, 18]. The major mechanism by which anandamide inhibits Tcurrent relies on an important hyperpolarized shift of the steady-state inactivation curve (∼10–12 mV) resulting in 85 % inhibition at holding potential (HP) −70 mV, whereas the inhibition was only 8 % at HP −110 mV [15]. In addition, anandamide accelerates the inactivation kinetics of CaV3 currents and especially of CaV3.3 current, resulting in 50 % inhibition of CaV3.3 current with 100 nM anandamide during action potential clamp mimicking thalamo-cortical relay cell activity (compared to an IC50 value of 1.1 μM during classical voltage clamp experiments) [15]. Anandamide and methanandamide (but not WIN 55,212-2) also inhibit native T-currents in NG108-15 cells independently of CB receptors [15]. In these cells, CaV3.2 channels are involved in neuronal differentiation relating to an autocrine mechanism that promotes neuritogenesis [16, 17]. Interestingly, in the presence of the CB1 antagonist SR141716A, anandamide reduced the number of cells expressing neurites by ∼60 %, indicating O

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Fig. 3 Effect of anandamide derivatives on T-currents. a Schematic chemical structure and effects at 10 μM of arachidonoyl ethanolamide (anandamide, AEA) and related compounds on CaV3.3 current. Critical regions for T-channels inhibition is indicated by colors (blue for the hydroxyl group, red for the amide linkage, and green for the alkyl chain).

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AEA derivatives are R1- and R2-methanandamide (R1- and R2methAEA), arachidonic acid (AA), arachidonyl alcohol (AA-OH), arachidonamide, ANMA, ACEA, arachidonic acid methyl ester (AA methyl ester), ethanolamine EA, and acetyl EA. Adapted from reference [18]

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As previously observed with poly-unsaturated fatty acids, other poly-unsaturated N-acylethanolamides also inhibit Tcurrents, and their effects increase with the number of double bonds. Saturated N-acylethanolamides, including palmitoyl ethanolamide (16:0 EA, PEA), stearoyl ethanolamide (18:0 EA, SEA), arachidoyl ethanolamide (20:0 EA), and docosanoyl ethanolamide (22:0 EA), have negligible effect, whereas the inhibition is intermediate with linoleoyl ethanolamide (18:2 EA) and maximal with docosahexaenoyl ethanolamide (22:6 EA, DHEA) [18]. It is important to note that both 18:2 EA and 22:6 EA were identified in various mammalian and invertebrate tissues [8]. Recent studies have indicated a role of 22:6 EA in hippocampal development [46] as well as in prostate cancer proliferation [10]. Application of 22:6 EA in LNCaP cells, a prostate cancer cell line, induces antiproliferative effects independently of CB receptors [10]. LNCaP cells express CaV3.2 current which is upregulated during prostate cancer development and promotes the secretion of mitogenic factors that could participate in the progression of the disease [31]. Therefore, CaV3.2 current inhibition could account for the beneficial effects of 22:6 EA in prostate cancer. In addition, the phytocannabinoids THC and cannabidiol also inhibit recombinant CaV3 currents as well as native Tcurrents in acutely isolated mouse trigeminal ganglion neurons [78]. THC inhibits T-currents with IC50 values of 1.3, 1.5, and 4.2 μM for CaV3.2, CaV3.1, and CaV3.3 currents, respectively, whereas cannabidiol is more potent, inhibiting Tcurrents with IC50 values of 0.78, 0.82, and 3.7 μM for CaV3.2, CaV3.1, and CaV3.3 currents, respectively [78]. Interestingly, cannabidiol is not a CB receptor agonist [88], whereas it displays antinociceptive [24] and anticonvulsant activity [93] and disrupts sleep [61], suggesting again a role of T-channel inhibition in these effects.

The lipoamino-acids and lipo-neurotransmitters Lipoamino-acids and lipo-neurotransmitters are a class of bioactive lipids with structure and properties similar to anandamide. The first identified lipoamino-acid in mammalian tissues was N-arachidonoyl glycine (NAGly), which differs from anandamide by a single oxygen moiety (Fig. 4) [38]. Subsequently, several others lipoamino-acids were identified including N-arachidonoyl GABA (NAGABA), N-arachidonoyl serine (NASer), and N-arachidonoyl alanine (NAAla) as well as lipo-neurotransmitters, including N-arachidonoyl serotonin (NA-5HT), N-arachidonoyl taurine (NATau), and N-arachidonoyl dopamine (NADA) (Fig. 4) [8, 11, 23, 34, 100]. These lipids were also identified with various alkyl chains; the most representative contains a palmitoyl (16:0), a stearoyl (18:0), an oleoyl (18:1), a linoleoyl (18:2), and a docosahexaenoyl (22:6) [7, 11, 23].

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Among these molecules, the lipo-neurotransmitters NADA and NATau activate TRPV1, whereas NA-5HT is a TRPV1 inhibitor [23, 54]. In addition, NADA is also a CB receptor activator, whereas lipoamino-acids, including NAGly, have no effect at both CB1 and TRPV1 receptors but displays important antinociceptive effects in acute and chronic pain [23, 38, 103]. The biosynthesis of these classes of lipids relies on two proposed mechanisms. The first involves conjugation of arachidonic acid or arachidonyl CoA via cytochrome c with the amino acid/neurotransmitters [7, 56]. The second involves a modification of a parental compound, as anandamide for NAGly via the sequential enzymatic reaction of alcohol dehydrogenase and aldehyde dehydrogenase [7, 11]. Recent studies have demonstrated that T-channels are important target for lipoamino-acid and lipo-neurotransmitters, including NAGly, NAGABA, NASer, NAAla, NADA, NA5HT, and NATau, which inhibit T-currents in the whole-cell mode (Fig. 4) [3, 14, 32, 78] and in the outside-out configuration [3]. As observed with fatty acids and N-acylethanolamides, the effects of N-acyl glycine, N-acyl 5HT, and N-acyl dopamine are not restricted to eicosanoids, and lipids containing 18 and 22 carbons produce significant inhibition at micromolar concentration, which increase with the degree of unsaturation [14, 32, 78]. The inhibition induced by lipoamino-acids mostly relies on a hyperpolarized shift of the steady-state inactivation curve of Tcurrents, which induces their inhibition at physiological resting potentials. In contrast, some negligible effects are observed at very hyperpolarized resting potentials (−110 mV) [3, 14, 32, 78]. In addition, NAGly slows the recovery from inactivation of T-currents [14]. Both NAGly and NA-5HT strongly accelerate inactivation kinetics of CaV3.3 but not of CaV3.1 and CaV3.2 currents [3, 14, 32, 78]. Interestingly, NA-5HT and NAGly have distinct effect on the deactivation kinetics of CaV3.3 current (but no effect on CaV3.1 and CaV3.2 currents), which is accelerated by NA-5HT and slowed by NAGly [14, 32]. NAGly is widely distributed among mammalian tissues and particularly in the pain neuraxis, including the skin, the spinal cord, and the brain [38]. NAGly causes analgesia in the hot plate test and suppresses inflammation-induced pain [23, 38, 85, 103], and recent pieces of evidence indicate that these effects rely on CaV3.2 inhibition. NAGly inhibits native Tcurrents in mouse trigeminal neurons [77] and lumbar dorsal root ganglion neurons with few effects on high-voltageactivated (HVA) Ca2+ currents and sodium currents [3]. In these sensory neurons, T-current (CaV3.2 related) promote neuronal activities by lowering the action potential threshold [63, 64], and agents that enhance T-currents (as L-cysteine) induce a thermal and mechanical sensitization, whereas inhibitors produce an analgesia [64, 91]. In line herewith, NAGly evoked a thermal analgesia in mice when injected in the hind paw (Fig. 4e). Furthermore, the analgesic effects of NAGly are abolished in CaV3.2 knockout (KO) mice, indicating the

694 Fig. 4 Effect of lipoamino-acids and lipo-neurotransmitters on Tcurrents: implication in pain perception. a Inhibition of CaV3.2 current by 3 μM N-arachidonoyl glycine (NAGly) and current recovery after washout with a BSA solution. b Dose dependence of CaV3.1, CaV3.2, and CaV3.3 current inhibition by NAGly. c, d Schematic chemical structure (c) and effect on CaV3.2 current (d) of several lipoaminoacids and lipo-neurotransmitters. e, f Effects of a vehicle and a NAGly solution on thermal pain (46 °C) when injected in the hindpaw in WT (e) and CaV3.2 KO mice (f). Results are expressed as the paw withdrawal latency (PWL) as a function of the time after injection. The “Pre” values represent the values obtained before injection. Adapted from references [3] and [14]

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role of the T-current inhibition (Fig. 4f) [3]. Similar findings were obtained with NAGABA-OH, a putative endogenous lipoamino-acid that strongly inhibits CaV3.2 currents (IC50 ∼210 nM) and induces a strong analgesia similar to the effect of morphine [3]. Interestingly, BSA, which removes T-current inhibition by lipoamino-acids in electrophysiological experiments [3, 14, 32], induced a thermal hyperalgesia in WT mice but not in CaV3.2 KO mice, suggesting a tonic T-current inhibition “in vivo” and its potential implication in the control of the pain pathway [3].

Arachidonic acid metabolites As exemplified with AA, lipids inhibiting T-currents, including AA and ω3 polyunsaturated fatty acids and anandamide

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and NAGly, contained at least a cis-1,4-pentadiene unit (– C=C–C=C–) and therefore are potentially metabolized in mammalian cells by COX, LOX, and the P450 epoxygenases, leading to the formation of prostaglandins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids (HETEs), and EETs (Fig. 5a) [12, 30, 33, 42, 76, 105]. These other important classes of signaling molecules are more specifically implicated in vascular constriction/dilatation and inflammation [12, 30, 33, 42, 76, 105]. A recent study has investigated the effects of the major COX, LOX, and cytochrome P450 epoxygenase products on the three human recombinant CaV3 channels (Fig. 5) [13]. It was demonstrated that the principal COX products, including prostaglandin E2 (PGE2) that is implicated in inflammation and fever [30], its metabolite 15-keto PGE2, and thromboxane B2 (TXB2), the stable metabolite of TXA2 that induces

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Fig. 5 Potent inhibition of Tcurrent by 5,6-EET: implication in vasodilation. a Schematic pathways of AA metabolism. b Inhibition of CaV3.2 current by 5,6-EET and current recovery after washout with a BSA solution. c Effects of COX, LOX, and P450 epoxygenase metabolites as compared to those of AA on CaV3 currents. d Constriction of second-order mesenteric arteries induced by phenylephrine (PE) in the presence of nifedipine alone or in association with 5,6-EET in WT and KO mice for CaV3.1 and of CaV3.2. Adapted from reference [13]

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vasoconstriction, all have negligible effect on T-currents (Fig. 5c) [13]. Similar results were found with the LOX metabolite leukotrienes, which promote inflammation and contribute to the pathology of asthma [30, 33], as assessed by leukotriene B4 (LTB4, the stable product of LTA4 produced by LTA4 hydrolase) or 5,6-dihydroxy-eicosatetraenoic acid, 5,6-DiHETE, the corresponding diol produced by hydrolyzing of LTA4 (Fig. 5c) [13]. In contrast, the precursor of leukotrienes, 5-hydroperoxy-eicosatetraenoic acids, and 5HPETE induces a significant inhibition of the three CaV3 currents with different potency among CaV 3 isoforms (CaV3.2 > CaV3.1 > CaV3.3), but this inhibition is weaker than those produced by AA (Fig. 5c) [13]. In the same way, the 5-HPETE metabolite, 5-HETE, produces a significant inhibition of the three Cav3 currents but to a lesser extent than those obtained with 5-HPETE. Similar results were found with the 12-LOX products 12-HPETE and 12-HETE on the three CaV3 currents (Fig. 5c). It should be noted that 5HPETE accelerates the inactivation kinetics of CaV3.3 current without significant effect on the inactivation kinetics for CaV3.1 and CaV3.2 currents [13].

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The P450 epoxygenase products were also studied leading to the discovery that EETs modulate CaV3 currents, in particular 5,6-EET, which induces more inhibition than AA (IC50 = 0.54 μM for the CaV3.2 current) (Fig. 5b). In contrast, 8,9-EET and 14,15-EET produced a smaller inhibition than AA on the three CaV3 currents but have relevant effects on CaV3.2 current (Fig. 5c) [13]. The 5,6-EET strongly inhibits CaV3.1, CaV3.2, and CaV3.3 currents in the minute range, and this effect is reversed by a bovine serum albumin perfusion (Fig. 5b). As previously observed with AA, the inhibition of Cav3 currents by 5,6-EET occurs at all potentials, and 5,6-EET modestly affects the voltage dependence of activation. Importantly, 5,6-EET induces a shift of the steady-state inactivation properties of T-currents toward negative potentials leading to inhibition at physiological resting potentials. As observed with AA current [87], a part of the 5,6-EET inhibitory effect (∼25 %) is independent of the voltage and cannot be explained by the shift of the steady-state inactivation curve, as assessed at HP −110 mV. In addition, 5,6-EET accelerates the inactivation kinetics of CaV3.1 and CaV3.3 current without significant effect on the inactivation kinetics for CaV3.2 current [13].

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T-channels (both CaV3.1 and CaV3.2) are expressed in several vascular tissues, including cerebral, renal, and mesenteric, and contribute in combination with L-type Ca2+ channels to the vascular tone [6, 9, 35, 44, 48, 73]. In vascular tissues, epoxygenase enzymes are widely present in both endothelial and vascular smooth muscle cells, and EETs induce vasodilation in several arterioles, including cerebral, renal, and intestinal [42, 76]. Therefore, EETs were proposed to be endothelium-derived hyperpolarizing factors (EDHF) by acting on smooth muscle Ca2+-activated K+ channels (KCa) [42, 76]. In addition, EETs, and especially 5,6-EET [104], were shown to directly activate TRPV4, which in turn activates KCa to induce vasodilation [28, 84, 102]. Using CaV3.1 and CaV3.2 KO mice, it was demonstrated that the constriction of second order mesenteric arteries induced by an α1-adrenergic receptor agonist in the presence of the L-type Ca2+ channel blocker nifedipine is reversed by 5,6EET in WT and CaV3.1 KO mice but not in CaV3.2 KO mice (Fig. 5d) [13]. Therefore, in these arteries, the constriction present after L-type Ca2+ channel blockade is dependent of CaV3.2 [37] and could be reversed by 5,6-EET. These findings are reminiscent to those obtained by the group of Kevin Campbell, which demonstrates that the relaxation in response to acetylcholine was impaired in CaV3.2 KO mice [21]. Importantly, acetylcholine acts on endothelial cells and promotes the liberation of vasodilatory factors, including EETs [12, 42]. It should be noted that T-channel expression and involvement in vascular function increase in small-diameter arteries [35, 44, 48] where myoendothelial coupling and relaxation by EDHF (including EETs) is more prominent [39, 42, 62, 76]. Considering that Cav3.2 is expressed in cerebral arteries and contributes to vasoconstriction [6, 9, 35, 44, 48, 73] whereas acetylcholine induced vasorelaxation of cerebral blood vessels [41, 42, 76], inhibition of T-currents by EDHF could account for the dilatation of several arteries, especially in the small cerebral arterioles.

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This possibility was further confirmed in a recent study using the synthetic radioactive compound [3H]-TTA-A1, a TTA-A2 derivative. TTA-A2 is a potent and specific synthetic inhibitor of T-current [47, 74, 94, 95] that acts in a similar way that of endogenous lipids: TTA-A2 inhibits the Cav3 current at physiological HP but not at very negative potentials (i.e., −110 mV) by inducing a negative shift in the steady-state inactivation properties [29, 47]. In addition, TTA-A2 slows the recovery from inactivation of T-currents [29, 47], as observed with lipids. Using radioactive binding assays with [3H]-TTA-A1, it was found that poly-unsaturated lipids which inhibit the CaV3.3 current, as arachidonic acid, anandamide, NAGly, NASer, NADA, NATau, NA-5HT, and 5,6-EET, all displaced [3H]-TTA-A1 binding with Ki in a micromolar or sub-micromolar range, whereas lipids with a saturated alkyl chain or PGE2, which did not inhibit the CaV3.3 current, had no effect (Table 1) [14]. These results indicate that TTA-A2 and lipids bind directly at the CaV3.3 protein at a same or an overlapping site. It should be noted that several other structurally unrelated T-channel inhibitors, including mibefradil, flunarizine, and pimozide, which also exhibit similar statedependent inhibition of T-currents [55, 79], were shown to interact with [3H]-TTA-A1 binding to membranes containing CaV3.3 [95], further highlighting the importance of this putative site at the CaV3 protein. These findings were confirmed in electrophysiological studies, in which bioactive lipids occluded TTA-A2 effect on CaV3.3 current [14]. In addition, TTAQ4, a positive allosteric modulator of [3H]-TTA-A1 binding and TTA-A2 functional inhibition, acts in a synergistic manner to increase lipid-induced inhibition of the Cav3.3 current [14], raising the interesting possibility that natural compounds exhibiting TTA-Q4 properties could exist and promote bioactive lipid effect on T-currents. In this context, it should be noted that palmitoyl ethanolamide and oleoyl ethanolamide increase the binding and the potency of anandamide at CB1

Table 1 Displacement of [3H]-TTA-A1 binding to CaV3.3 expressing membrane, expressed as Ki. Adapted from reference [14]

Inhibition by bioactive lipids: direct or indirect effects? Several pieces of evidence suggest that bioactive lipids inhibit T-currents directly. The inhibition is observed for low concentration of lipids (below the micellar concentration) and observed in cell-free outside-out/inside-out patches. In addition, the unrelated synthetic compounds trinitrophenol and dinitriphenol, which also are anionic amphipathic molecules and cause a membrane crenation similar to those of AA [68, 81, 82], induce a small increase in CaV3 currents but no inhibition [18]. Similar findings were obtained with a hypoosmotic solution that also mimics arachidonic acid crenator effects on cell membrane, suggesting that bioactive lipids act at the CaV3 protein directly [18].

Lipids

Ki (μM)

N-arachidonoyl ethanolamide (AEA, 20:4) N-arachidoyl ethanolamide (20:0 EA)

1.35±0.04 No effect (40 μM)

N-arachidonoyl glycine (NAGly, 20:4) N-arachidoyl glycine (20:0 Gly) N-arachidonoyl L-serine (NASer, 20:4) N-arachidonoyl taurine (NATau, 20:4) N-arachidonoyl serotonin (NA-5HT, 20:4) N-arachidonoyl dopamine (NA-5HT, 20:4) Arachidonic acid (AA, 20:4) 5,6-epoxyeicosatrienoic acid (5,6 EET) Prostaglandin E2 (PGE2)

7.12±0.31 No effect (40 μM) 9.02±0.06 4.13±0.11 0.026±0.001 0.170±0.004 0.42±0.02 0.24±0.01 No effect (40 μM)

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and TRPV1 receptors, a phenomenon called the “entourage” effect [5, 36]. Overall, these results demonstrate a common molecular mechanism for the synthetic T-channel inhibitors and the endogenous lipids and indicate that TTA-A2 and TTA-Q4 could be important pharmacological tools to dissect the involvement of T-current in the physiological effects of endogenous lipids. Remarkably, TTA-A2 had important pharmacological effects similar to those of bioactive lipids as in epilepsy [74, 94], pain [29], and sleep [47, 74, 94].

Concluding remarks Since a decade, numerous endogenous lipids were identified in mammalian tissues where they participated to cell communication and signaling and mediated diverse physiological function. As reviewed here, many studies have indicated that multiple bioactive lipids inhibit T-current, which could mediate their pharmacological effect, as demonstrated in analgesia and vasodilation. However, in these studies, the lipids are exogenously applied on cells and tissues or injected in animals, but none of these studies provide evidence for direct inhibition of T-currents by endogenously produced signaling lipids. Several studies have indicated that Gq protein-coupled receptors, especially muscarinic receptors, promote PLA2 activation and release of arachidonic acid, which induces complex effects on HVA Ca2+ currents [75]. In addition, the activation of muscarinic and purinergic receptors as well as cellular stress induces anandamide formation and subsequent TRPV1 activation in sensory neurons [97]. Therefore, it will be of great interest to investigate whether these pathways could lead to the inhibition of T-currents. Furthermore, future in vivo studies should manipulate the enzymes implicated in lipid metabolism (as FAAH) and investigate the role of Tcurrent in the resulting behavioral responses to decipher whether endogenously produced lipids mediated their functions via T-current inhibition.

Conflict of interest The authors declare that they have no conflict of interest.

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Modulation of T-type calcium channels by bioactive lipids.

T-type calcium channels (T-channels/CaV3) have unique biophysical properties allowing a calcium influx at resting membrane potential of most cells. T-...
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