Synaptic lipid signaling

Bazán, Nicolás G.

doi:10.1194/jlr.r300013-jlr200

Cited by 230 publications

(50 citation statements)

References 139 publications

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“…Polyunsaturated fatty acids and N-acyl ethanolamides are signaling molecules implicated in a multitude of physiological and pathophysiological events, including cardiac and neuronal excitability (31,33,40,42), cardioprotection and neuroprotection from ischemic and epileptic episodes (31, 34 -36, 40), inflammation, and pain (32,39). Considering the role of T-channels in cardiac and neuronal pacemaker (1, 2, 13, 14), cardiac hypertrophy (15), neuroprotection, and absence epilepsy (8,9,67) as well as in pain perception (10 -12), it is attractive to suggest that T-channel inhibition may contribute to polyunsaturated fatty acid and N-acyl ethanolamide effects.…”

Section: Discussionmentioning

confidence: 99%

“…Anandamide (N-arachidonoyl ethanolamide, AEA) 2 belongs to a new major class of small lipid messengers, including endocannabinoids and N-acyl-related molecules, eicosanoids, and fatty acids (22, 28 -32). These bio-active lipids are involved in a multitude of physiological and pathophysiological events, including neuronal excitability (22,23,31,33), sleep (34), epilepsy and neuroprotection (34 -37), inflammation and pain (28,29,32,38,39), as well as cardiovascular modulation (40 -42), fertilization, and cell cycle progression (38,43,44). Despite the fact that both small lipid messengers and T-channels display similar physiological functions (but with opposite effects), little is known about the properties and the specificity of this new class of molecules on the three Ca V 3 channels.…”

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Chemical Determinants Involved in Anandamide-induced Inhibition of T-type Calcium Channels

Chemin

Nargeot

Lory

2007

Journal of Biological Chemistry

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Anandamide, originally described as an endocannabinoid, is the main representative molecule of a new class of signaling lipids including endocannabinoids and N-acyl-related molecules, eicosanoids, and fatty acids. Bioactive lipids regulate neuronal excitability by acting on G-protein-coupled receptors (such as CB1) but also directly modulate various ionic conductances including voltage-activated T-type calcium channels (T-channels). However, little is known about the properties and the specificity of this new class of molecules on their various targets. In this study, we have investigated the chemical determinants involved in anandamide-induced inhibition of the three cloned T-channels: Ca V 3.1, Ca V 3.2, and Ca V 3.3. We show that both the hydroxyl group and the alkyl chain of anandamide are key determinants of its effects on T-currents. As follows, T-currents are also inhibited by fatty acids. Inhibition of the three Ca V 3 currents by anandamide and arachidonic acid does not involve enzymatic metabolism and occurs in cell-free inside-out patches. Inhibition of T-currents by fatty acids and N-acyl ethanolamides depends on the degree of unsaturation but not on the alkyl chain length and consequently is not restricted to eicosanoids. Inhibition increases for polyunsaturated fatty acids comprising 18 -22 carbons when cis-double bonds are close to the carboxyl group. Therefore the major natural (food-supplied) and mammalian endogenous fatty acids including ␥-linolenic acid, mead acid, and arachidonic acid as well as the fully polyunsaturated 3-fatty acids that are enriched in fish oil eicosapentaenoic and docosahexaenoic acids are potent inhibitors of T-currents, which possibly contribute to their physiological functions.Voltage-dependent calcium channels comprise three families: the L-type channels (Ca V 1 family), the neuronal N-, P/Q-, and R-type channels (Ca V 2 family), and the T-type channels (Ca V 3 family). The electrophysiological features of T-type Ca 2ϩ channels (T-channels) are low voltage-activated Ca 2ϩ currents, low unitary conductance, fast inactivation and slow deactivation kinetics, and strong steady-state inactivation at physiological resting potentials (1, 2). Three T-channel subunits have been identified: Ca V 3.1 (or ␣ 1G ), Ca V 3.2 (or ␣ 1H ), and Ca V 3.3 (or ␣ 1I ) (2). In mammalian expression systems, the Ca V 3.1 and Ca V 3.2 currents share typical properties of native T-channels, while Ca V 3.3 currents display unusually slow inactivation kinetics, which are characteristic of specific neurons (1-3). These three subunits are also subject to alternative splicing, which influences their electrophysiological properties (4 -6). The Ca V 3.1 and Ca V 3.2 subunits are widely expressed in various tissues, mainly in the heart and in the nervous system, whereas Ca V 3.3 is restricted to the central nervous system (2). In the nervous system, T-channels generate low threshold spikes and participate in spontaneous firing (1, 2). They are involved in slow wave sleep (7), in absence epilepsy (8, 9),...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Chemical Determinants Involved in Anandamide-induced Inhibition of T-type Calcium Channels

Chemin

Nargeot

Lory

2007

Journal of Biological Chemistry

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“…Several genes have been reported to be activated by dietary long-chain PUFA, and some gene products, alone or in combination with the membrane effects of these PUFA, exert their beneficial effect on neural functions such as learning and memory. The fact that ALA and DHA activate several genes in other tissues, like liver or adipose tissue, is well known (40)(41)(42)(43)(44)(45), but the underlying molecular mechanisms of the direct effects of PUFA diet-induced gene-expression changes in the brain have been addressed by very few studies (46)(47)(48)(49)(50)(51)63).…”

Section: Effect Of Dietary Omega-3 Pufa On Gene Expression In the Brainmentioning

confidence: 99%

Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression

Kitajka

Sinclair

Weisinger

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

281

166

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Polyunsaturated fatty acids (PUFA) are essential structural components of the central nervous system. Their role in controlling learning and memory has been well documented. A nutrigenomic approach with high-density microarrays was used to reveal brain gene-expression changes in response to different PUFA-enriched diets in rats. In aged rats fed throughout life with PUFA-enriched diets, genes with altered expressions included transthyretin, ␣-synuclein, and calmodulins, which play important roles in synaptic plasticity and learning. The effect of perinatal omega-3 PUFA supply on gene expression later in life also was studied. Several genes showed similar changes in expression in rats fed omega-3-deficient diets in the perinatal period, regardless of whether they or their mothers were fed omega-3 PUFA-sufficient diets after giving birth. In this experiment, among the down-regulated genes were a kainate glutamate receptor and a DEAD-box polypeptide. Among the up-regulated genes were a chemokine-like factor, a tumor necrosis factor receptor, and cytochrome c. The possible involvement of the genes with altered expression attributable to different diets in different brain regions in young and aged rats and the possible mode of regulatory action of PUFA also are discussed. We conclude that PUFA-enriched diets lead to significant changes in expression of several genes in the central nervous tissue, and these effects appear to be mainly independent of their effects on membrane composition. The direct effects of PUFA on transcriptional modulators, the downstream developmentally and tissue-specifically activated elements might be one of the clues to understanding the beneficial effects of the omega-3 PUFA on the nervous system.

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“…Several reports suggested that DHA may also prevent apoptosis in neurons (6). AA is believed to function directly as a signaling molecule and is a precursor of several eicosanoid molecules that also have signaling functions within the nervous system (7).…”

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confidence: 99%

Acyl-CoA Synthetase 2 Overexpression Enhances Fatty Acid Internalization and Neurite Outgrowth

Marszalek

Kitidis

Dararutana

et al. 2004

Journal of Biological Chemistry

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During neurodevelopment neurons increase phospholipid synthesis to generate additional plasma membrane that makes up the growing neurites. Compared with most cell types, neurons contain a high percentage of the polyunsaturated fatty acids (PUFAs) arachidonic acid (AA) and docosahexaenoic acid (DHA). By utilizing PC12 cell lines as a model neuronal cell line, we examined the internalization rate of AA, DHA, and non-essential oleic acid (OA), as well as their effects on neurite outgrowth. When wild type cells were differentiated, the rate of AA and DHA internalization increased 50% more than the rate of OA internalization. When media were supplemented with AA or DHA, the average neurite length was increased by ϳ40%, but supplementation with the same amount of OA had no effect. We also increased the levels of acyl-CoA synthetase-1 (ACS1) and ACS2 proteins to determine whether they contribute to PUFA internalization or neurite outgrowth. Overexpression of ACS1 increased the rate of OA internalization by 55%, and AA and DHA uptake was increased by 25%, but there was no significant change in neurite outgrowth. In ACS2-overexpressing cells, in contrast, the rate of OA internalization increased by 90%, AA by 115%, and DHA by 70%. The average aggregate neurite length in ACS2-overexpressing cells was increased by ϳ40% when the media were supplemented with PUFAs, but there was no change with OA supplementation. Taken together, these results support the hypotheses that ACSs are rate-limiting for fatty acid internalization and that ACS2 enhances neurite outgrowth by promoting PUFA internalization.Fatty acids (FAs) 1 are utilized by the body as an energy source, function as signaling molecules, and are a structural component of membranes. The length of a FA and the amount and position of double bonds within that FA greatly influence its solubility and flexibility. The type of FA utilized is often linked to the primary function of the cell. For example, the primary function of skeletal and cardiac muscle is force generation, which requires enormous amounts of energy. Therefore, saturated and unsaturated FAs liberated from triglycerides (TAGs) or imported as free FAs from blood are interchangeably utilized via ␤-oxidation to generate ATP to power myosin movement. Adipocytes, on the other hand, are a storage depot for energy and therefore primarily function in the generation of TAGs from saturated and unsaturated free FAs that are stored in lipid droplets within the cell.

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Synaptic lipid signaling

Cited by 230 publications

References 139 publications

Chemical Determinants Involved in Anandamide-induced Inhibition of T-type Calcium Channels

Chemical Determinants Involved in Anandamide-induced Inhibition of T-type Calcium Channels

Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression

Acyl-CoA Synthetase 2 Overexpression Enhances Fatty Acid Internalization and Neurite Outgrowth

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