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Docosahexaenoic acid (DHA) and arachidonic acid (AA) are found in high concentrations in brain cell membranes and are important for brain function and structure. Studies suggest that AA and DHA are hydrolyzed selectively from the sn-2 position of synaptic membrane phospholipids by Ca2+-dependent cytosolic phospholipase A2 (cPLA2) and Ca2+-independent phospholipase A2 (iPLA2), respectively, resulting in increased levels of the unesterified fatty acids and lysophospholipids. Cell studies also suggest that AA and DHA release depend on increased concentrations of Ca2+, even though iPLA2 has been thought to be Ca2+-independent. The source of Ca2+ for activation of cPLA2 is largely extracellular, whereas Ca2+ released from the endoplasmic reticulum can activate iPLA2 by a number of mechanisms. This review focuses on the role of Ca2+ in modulating cPLA2 and iPLA2 activities in different conditions. Furthermore, a model is suggested in which neurotransmitters regulate the activity of these enzymes and thus the balanced and localized release of AA and DHA from phospholipid in brain, depending on the primary source of the Ca2+ signal.
Although PLA2 enzymes have been known for over 100 years, only within the last 15 years has their importance for neurochemical processes been widely recognized . These enzymes catalyze the hydrolysis of esterified fatty acids at the stereospecifically numbered (sn)-2 position of membrane phospholipids to release unesterified fatty acids and form lysophospholipids [2–9]. The fatty acids and their metabolic products are important for normal brain function and can alter neuropathological processes [1, 10–15].
PLA2s are classified according to their sequence homology and Ca2+ dependence. They belong to three main families having different catalytic sequences, and these sequences are conserved among PLA2s in the same family. The three most described families are: low molecular mass secretory PLA2 (sPLA2), higher molecular mass Ca2+-dependent cytosolic PLA2 (cPLA2), and “Ca2+-independent” PLA2 (iPLA2) (See Table 1). Other less studied PLA2 families have been described, such as platelet-activating factor-acetyl hydrolase (PAF-AH) [8, 21] and lysosomal PLA2 [22, 23].
The sPLA2 family is subdivided into groups: sPLA2-IB, sPLA2-IIA, sPLA2-IIC, sPLA2-IID, sPLA2-IIE, sPLA2-IIF, sPLA2-III, sPLA2-V, sPLA2-X, and sPLA2-XII . The genes for human sPLA2–IB map to chromosome 12q23–24, those for group II subfamily sPLA2s (IIA, IIC, IID, IIE, IIF) and for sPLA2-V map to chromosome 1p34–36, and the gene for sPLA2-X maps to chromosome 16p12–13 . sPLA2s are Ca2+-dependent for catalytic activity (generally requiring millimolar Ca2+ concentrations) [1, 25, 26], consistent with their extracellular activity and millimolar Ca2+ concentrations in the extracellular space . Evidence also points to an intracellular functional role sPLA2 in caveolae-containing compartments around the nucleus of immune cells and in the nucleus of astrocytes and neurons [28–30].
The cPLA2 family is subdivided into cPLA2α, cPLA2β, cPLA2γ, cPLA2δ, cPLA2 and cPLA2ζ, which also are referred to as groups IVA, IVB, IVC, IVD, IVE and IVF, respectively. They are coded by gene on different human chromosomes, chromosome 1 (cPLA2α), 15 (cPLA2β, cPLA2δ, cPLA2, cPLA2ζ) and chromosome 19 (cPLA2γ), which are not the same as the chromosomes that code for the sPLA2 family [31–38]. cPLA2 becomes activated after translocating to the plasma membrane from the cytosol, and is constitutively membrane-bound [1, 38]. Although Ca2+ is not necessary for cPLA2 catalytic activity, nanomolar Ca2+ concentrations are needed for its binding to the membrane, where other enzymes that regulate the arachidonic acid (AA) cascade, including cyclooxygenases (COXs) and lipoxygenases, also are located .
The iPLA2s have extremely different structures compared to the cPLA2 and sPLA2 families . They occur in numerous splicing variants, only some of which are functional. iPLA2s are classified as group VI and are subdivided into VIA and VIB, or into iPLA2β and iPLA2γ, respectively. Each iPLA2 is coded by a different chromosome, iPLA2β is coded by chromosome 23q13  and iPLA2γ is coded by chromosome 7q31 [1, 41]. iPLA2β is unique among PLA2s, as it has multiple ankyrin repeats, which are common motifs found in more than 400 proteins, including cell cycle regulators and transcription factors. Ankyrin repeats have been implicated in protein–protein interactions and can influence many physiological functions . A site near the C-terminus of some iPLA2β variants can bind to calmodulin with the help of Ca2+ [1, 42–44].
The PAF-AHs are classified as VIIA (lipoprotein-associated- PLA2), VIIB (PAF-AH II) VIIIA (PAF-Ib) and VIIIB (PAF-Ib or VIIIB forms a heterodimer with VIIIA) . PAF-AH was first named for its ability to cleave the acetyl group from the sn-2 position of platelet activating factor (PAF); however, this enzyme can cleave oxidized lipids in the sn-2 position up to 9 carbons long, not just PAF. This enzyme also has been shown to access substrate in the aqueous phase, unlike the other PLA2s studied , in a Ca2+-independent fashion . Type I PAF-AH is a complex of two catalytic subunits, alpha1 and alpha2, a regulatory beta subunit, and a gamma subunit . Its structure is very similar to the structure of G proteins , whereas type II PAF-AH is a single polypeptide . Type II PAF-AH is myristoylated at the N-terminus and distributed in both the cytosol and membranes. Plasma PAF-AH has a closed structure when compared to II PAF-AH, and exists in association with plasma lipoproteins .
Lysosomal or group XV PLA2 is a calcium-independent PLA2 enzyme of 25 kDa , which has a distinguishing characteristic of having its maximal activity in an acidic medium, and accordingly, it also is called acidic iPLA2 [23, 48].
This review will focus on the roles of the cPLA2 and iPLA2 in mammalian brain. We propose a model for receptor-mediated regulation of PLA2 enzyme activities by Ca2+ signals originating from intracellular and extracellular sources, leading to the controlled, balanced and localized release of specific fatty acids as signaling molecules.
cPLA2 is found in mammalian brain in three different forms: cPLA2α (85-kDa), cPLA2β (114-kDa), and cPLA2γ (61-kDa). cPLA2β is found mainly in the cerebellum, whereas cPLA2α and cPLA2γ are uniformly distributed in rat brain [16, 31, 33]. cPLA2α is found both in astrocytes and neurons . In neurons of rat brain, cPLA2 has been localized at post-synaptic sites, suggesting that it is important in neurotransmission (see table 2) .
iPLA2 is believed to account for more than 70% of brain PLA2 activity . iPLA2β (80-kDa) was purified from rat brain  and found in all brain regions, with the highest activity in striatum, hypothalamus, and hippocampus [16, 49]. Similarly, two different iPLA2s (110-kDa and 39-kDa) were purified from bovine brain [51, 52]. iPLA2 (85-kDa) also was identified in monkey brain, in the neocortex, amygdala, hippocampus, caudate nucleus, putamen, and nucleus accumbens, whereas in the thalamus, hypothalamus and globus pallidus it was lightly labeled (see table 2). On the other hand, the midbrain, vestibular, trigeminal and inferior olivary nuclei, and the cerebellar cortex were densely labeled . Individual iPLA2 subtypes have not been investigated in the bovine or monkey brain. The enzyme is present in astrocytes  and in neurons, where its localization in dendrites and axon terminals suggests that it plays a role in neuronal signaling .
Arachidonic acid (AA, 20:4n-6), an n-6 polyunsaturated fatty acid (PUFA), comprises approximately 5–15% of total fatty acids in most tissue phospholipids . It can be synthesized in the liver from dietary derived linoleic acid, or obtained directly from dietary sources . AA is preferentially released from phospholipid by cPLA2 [1, 4, 56]. It and its metabolites (prostaglandins, leukotrienes, thromboxanes, lipoxins) in brain influence synaptic signaling [57, 58], neuronal firing , neurotransmitter release , activation of intracellular receptors , hypothalamic-pituitary function , nociception , gene expression , cerebral blood flow , circadian rhythm , and appetite , among other targets. Altered AA metabolism has been implicated in neuronal death  and in a number of neurological, neurodegenerative, and psychiatric disorders, including epilepsy , ischemia, stroke , HIV-associated dementia , amyotrophic lateral sclerosis , Alzheimer disease , Parkinson disease , schizophrenia , bipolar disorder [74–76] and depression [77, 78].
Docosahexaenoic acid (DHA, 22:6n-3) is the most abundant n-3 PUFA in brain and is necessary for normal brain function . Esterified DHA within membrane phospholipids is hydrolyzed preferentially by iPLA2 .
Humans can obtain DHA by eating fish or fish products, or can synthesize it in the liver from circulating α-linolenic acid, through serial steps of desaturation, elongation and oxidation [55, 80]42]. Dietary restriction of n-3 PUFAs in animal models decreased brain DHA content while increasing concentrations of the elongation product of AA, docosapentaenoic acid (22:5n-6) [80–82]. Rats deprived of dietary n-3 PUFAs for 15 weeks had increased brain mRNA, protein and activity levels of cPLA2, sPLA2 and COX-2, but decreased expression of iPLA2 and COX-1 .
DHA has been found important for membrane function and fluidity, photoreceptor function , memory [84, 85], problem solving , and developmental visual and sensory functions . Some studies but not others indicate that dietary DHA supplementation is beneficial in a number of brain disorders [87, 88]. In rats, dietary n-3 PUFA deprivation for 15 weeks increased aggression and depression scores on behavioral tests . DHA, like AA, can be metabolized by COX and lipoxygenase enzymes and generate active compounds [90, 91]. DHA products, in contrast to AA products, seem to have a beneficial effect in inflammatory and neurodegenerative conditions. Resolvins of the D series and docosatrienes, which are bioactive DHA products that possess potent anti-inflammatory, immunoregulatory [92, 93], and neuroprotective actions , are termed neuroprotectins .
Activation of serotonin (5-HT) 5-HT2A receptors in astroglioma cells caused DHA release from membrane phospholipids . Muscarinic receptor activation by arecoline also caused DHA release and plasma-derived DHA incorporation into rat brain synaptic membranes, consistent with its participation in neuronal signaling [102, 103].
DHA increased N-methyl-D-aspartate (NMDA) function in neurons. Both DHA and AA increased entry of extracellular Ca2+ into neurons via glutamatergic NMDA receptors, and DHA also increased the probability of NMDA channel opening . In another study, AA increased while DHA inhibited glutamate-induced prostaglandin release from astrocytes; DHA inhibited the AA effect .
Unesterified DHA can promote Ca2+ release from intracellular stores in the endoplasmic reticulum (ER) . Ca2+ released from the ER can be a continuous source of Ca2+ for mitochondria, can activate dehydrogenases and mitochondrial ATP synthesis and energy production, and can stimulate neuroprotective signals . On the other hand, Ca2+ uptake into mitochondria can modulate the activity of Ca2+ channels in the ER [108, 109]. If the balance between mitochondria and the ER is disturbed, a Ca2+ overload in the mitochondria can trigger necrosis or apoptosis .
Release of Ca2+ from intracellular stores via purinergic  or nicotinic  receptors can be neuroprotective. Intracellular Ca2+ release induced by isoflurane  or fructose-1,6-biphosphate was shown to be neuroprotective [114, 115]. Ca2+ release from the ER, induced by AA or DHA, reduced the peak of subsequent Ca2+ release induced by G protein activation, showing a complex relation between these two PUFAs and intracellular Ca2+ .
Neuroprotectin D1 is a metabolite of DHA that may account for part of the opposite effects of DHA and AA. The synthesis of neuroprotectin D1 was increased in cells exposed to the Ca2+ ionophore A23187 or to interleukin-1β, and depended on PLA2 activity . Both A23187 and interleukin-1β can induce Ca2+ release from intracellular stores . However, regulation by ER Ca2+ of neuroprotectin D1 synthesis induced by A23187 or interleukin-1β has not been studied. Neuroprotectin D1 also can inhibit β-amyloid production  and COX-2 expression . COX-2, which appears involved in neuroinflammation and is overexpressed in the Alzheimer disease brain [118, 119], converts AA to prostaglandins that also can increase β-amyloid production . COX-2 also has been implicated in multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease, and Creutzfeldt-Jakob disease . DHA in these conditions may modulate COX-2 activity and AA metabolite production via COX-2.
A DHA neuroprotective effect also is supported by evidence that iPLA2 inhibition increased neuronal death induced by reactive oxygen species . The data together suggest that increased iPLA2 activity and DHA release can be neuroprotective.
In other contexts, iPLA2 activation may have different consequences, related to its different subtypes, their location, and substrate availability in brain. In apoptotic cells, iPLA2γ seems necessary for mitochondrial membrane pore transition formation . iPLA2 is a substrate for caspase-3 (or other caspases), and is cleaved during the apoptotic process at the consensus Asp183. The resulting fragment, iPLA2(184-C), possesses the entire catalytic domain and seven of eight ankyrin repeats, and is functionally more active than intact iPLA2 in cells . On the other hand, inhibition of iPLA2β induced apoptosis in one study . The role of DHA in apoptosis related to iPLA2 inhibition is not known.
Preferential release of DHA and AA by iPLA2 and cPLA2, respectively [49, 74, 79], raises the possibility that the enzymes are controlled by separate mechanisms and serve different or even opposing functions . For example, pharmacological studies with chronic lithium, carbamazepine and valproate in unanesthetized rats, when combined with in vivo kinetic fatty acid modeling and molecular biology measurements, confirmed in vitro findings that cPLA2 is specific for AA release, whereas iPLA2 is comparatively specific for DHA release from phospholipid in brain synaptic membranes [74, 125, 126]
cPLA2 requires Ca2+ for its translocation and arachidonic acid release . Therefore, Ca2+ entry through ligand-gated ion channels, such as NMDA receptors, can activate this enzyme [127, 128]. In neurons, NMDA receptor activation induces Ca2+ entry from the extracellular space and activates cPLA2, and this activation is reversed by MK-801 (an NMDA antagonist), by removing calcium from the extracellular space, or by chronically administering lithium, valproic acid or carbamazepine, mood stabilizers effective in bipolar disorder, to rats [129, 130] [131, 132]. The cPLA2 coupling to Ca2+ entry through the membrane seems to depend on its location in the cell . The localization of Ca2+ entry appears more important than the pattern of Ca2+ entry. In this sense, single transients, repetitive oscillationrs or sustained plateaus of Ca2+ activate cPLA2. Under these circumstances, cPLA2 translocates to the nucleus where it promotes AA release. On the other hand, potassium-induced Ca2+ entry can induce depolarization and the opening of voltage-dependent Ca2+ channels located at sites close to neurotransmitter release. However, potassium depolarization does not activate AA release, probably because cPLA2 is not located close to releasing sites . In agreement with this evidence of Ca2+ dependence of neurotransmitter-induced cPLA2 activity, 5-HT receptor activation in hippocampal neurons induced an increase in PLA2-mediated AA release that was reversed by removing extracellular Ca2+ .
iPLA2 has been considered to be Ca2+-independent, because its catalytic activity was found to be independent of Ca2+ when studied in an incubation medium . However, in fractionated cytosol, Ca2+ later was shown to decrease iPLA2β activity, probably by modifying its interaction with calmodulin . Multiple contact points in the 15-kDa C-terminal portion of iPLA2β have been identified as determinants of its Ca2+-dependent interaction with calmodulin . Interaction between calmodulin and iPLA2 inhibits iPLA2 activity and is modulated by Ca2+ .
iPLA2β is highly localized in the ER in areas around the cell nucleus  and in the cytosol; it is less expressed near plasma membranes and mitochondria . iPLA2β immunoreactivity has been detected around the nuclear envelope in cortical and limbic areas of the rhesus brain , as well in dendrites and terminals, suggesting a local roles.
As illustrated in Figure 1, Ca2+ can be released from intracellular ER stores in several ways. The ER has two types of membrane receptors, an inositol-1,4,5-phosphate receptor (InsP3R), and a ryanodine receptor (RyR) that can receive information from the cytosol and release Ca2+ from the ER lumen. This signaling can be evoked by purinergic [136, 137], muscarinic , or metabotropic glutamatergic receptors , so as to produce receptor-mediated inositol-3-phosphate (InsP3) release and activate the InsP3R. Activation of NMDA receptors [140, 141], AMPA receptors , or even InsP3Rs  can release Ca2+ by “Ca2+-induced Ca2+ release” (CICR) through activation of RyRs. Inhibition of the reticular ATPase pump (SERCA) by thapsigargin, DBHQ (2,5-di(tert-butyl)hydroquinone), or Br(2)-TITU (1,3-dibromo-2,4,6-tris (methyl-isothio-uronium) benzene), also can cause a sustained release of Ca2+ from the ER by a different mechanism. Ca2+ is believed to be released on a continuous basis from the ER and refilled by SERCA. Blocking SERCA activity may, as a result, increase cytosolic Ca2+ concentrations (see Figure 1) . The Ca2+ released from intracellular stores by ATP, A23187, thapsigargin, or arginine vasopressin may activate iPLA2 [42, 145], even in the presence of intracellular or extracellular Ca2+ chelators such as BAPTA or EGTA, which suggests that ER calcium emptying can transiently modulate the enzyme availability by releasing iPLA2 from calmodulin binding .
Smooth muscle cells treated with the calmodulin inhibitor W-7 or with thapsigargin release AA from the same pool, suggesting that iPLA2β is bound to a calmodulin, and that calmodulin acts as a sensor of reticular Ca2+ to regulate iPLA2 activity [42, 44]. The PLA2 family is formed by ankyrins, and ankyrins are related to protein-protein interactions and may modulate regulation of iPLA2 activity by calmodulin . Moreover, thapsigargin increases iPLA2β expression in purified ER . Strokin et al. , who demonstrated the exclusive release of DHA by iPLA2, also showed that the ionophore A23187 increased DHA release 11-fold and AA release only 3.9 -fold compared to their respective baselines. In those studies, extracellular Ca2+ may have stimulated cPLA2 directly by increasing Ca2+ close to the plasma membrane, and have activated iPLA2 indirectly by releasing Ca2+ from intracellular stores by a CICR. ATP-induced AA release was suppressed by removing extracellular Ca2+ in that study, but DHA release was unchanged. Thus ATP could have induced Ca2+ release from intracellular stores to selectively activate iPLA2 [79, 147].
This putative modulation of iPLA2 activity and DHA release by ER Ca2+ release is further suggested by experimental studies of ischemia or oxygen and glucose deprivation (OGD). In mouse C2C12 myotubes, OGD increased 4-bromoenol lactone (BEL, an iPLA2 inhibitor)-sensitive iPLA2 activity that could be blocked by an siRNA against iPLA2β. iPLA2β protein in these cells was identified mainly at the endoplasmic reticulum, where it accumulated further during OGD, whereas the mRNA level was unchanged . In agreement with these results, DHA is released during decapitation-induced ischemia . Ca2+ entry from the extracellular space is a well-known source of intracellular Ca2+ during OGD. However, an important component of the Ca2+ increase is due to ER Ca2+ release, and particularly SERCA dysfunction is an important mechanism for ischemic Ca2+ overload [150, 151]. These results suggest that OGD may activate iPLA2 in the ER after ER Ca2+ release by the physical dissociation of iPLA2 from calmodulin.
Other evidence for the activation of iPLA2 by Ca2+ derived from the ER comes from a study of the iPLA2 effect on store operated calcium entry (SOCE). SOCE is another regulatory mechanism of Ca2+ homeostasis. It consists in the entry of Ca2+ from extracellular space that is induced by Ca2+ released from intracellular stores [152, 153]. In rat cerebellar astrocytes, iPLA2 is a major regulator of SOCE. During depletion of ER Ca2+ stores, iPLA2 is believed to be activated, resulting in opening channels in plasma membrane by the formation of lysophospholipids, which may affect the lipid environment of the channels or directly interact with them. In this regard, both depletion of ER Ca2+ stores and inhibition of calmodulin increased BEL-sensitive iPLA2 activity in cultured cerebellar astrocytes. Furthermore, the specific antisense inhibition of iPLA2 reduces the SOCE . This study, using antisense to inhibit iPLA2 and SOCE currents as the physiological outcome, is strong evidence that iPLA2 is indeed the PLA2 subtype that can be dissociated from calmodulin either by an inhibitor of calmodulin or by Ca2+ release from ER.
These results suggest Ca2-controlled activation of iPLA2 in vivo and different possibilities for neurotransmitter regulation of AA and DHA release and signaling, since many neurotransmitters are able to stimulate InsP3 formation or CICR. Given that Ca2+ in the ER lumen is believed to be regulated by specific proteins, changes in intracellular Ca2+ concentrations can transmit signals both to the ER surface and the lumen. For example, calreticulin is an ER chaperone that can detect changes in Ca2+ inside the ER and interact with other proteins to integrate Ca2+ release with different cell functions . Calmodulin, and possibly other Ca2+ sensitive proteins, may link ER Ca2+ release to iPLA2 activation. Ca2+ from these different sources, thus, may couple neurotransmission in different ways to iPLA2 and cPLA2 activities, thereby regulating DHA and AA signaling.
Agonist activation of dopaminergic D2 [155–157], serotonergic 5-HT2A/2C , NMDA or cholinergic muscarinic receptors [102, 103] has been shown to increase AA release from rat brain membrane phospholipids in vivo. Muscarinic and 5-HT2A receptor activation also increased DHA release in vivo or in vitro [101–103]. D2 and 5-HT2A/2C agonists can activate cPLA2 by a G protein mechanism [134, 159], whereas 5-HT agonists and NMDA agonists can do so by increasing cell entry of extracellular Ca2+, since cPLA2 is Ca2+-dependent [133, 134]. 5-HT2A receptor activation also can release Ca2+ from InsP3R stores , and muscarinic agonists can increase Ca2+ influx into the cell to also release Ca2+ from intracellular stores . Thus, Ca2+ from the two sources can separately control the activities of both cPLA2 and iPLA2, thereby regulating AA and DHA release from membrane phospholipids.
In many neurodegenerative, psychiatric diseases and in conditions having increased neuronal death, the modulation exerted by DHA in docosanoid production could reduce neuronal damage (see  for review). Inhibition by DHA of Ca2+ entry through L-type calcium channels could be a beneficial effect of DHA . Although a description of how differential activation of cPLA2 and iPLA2 by Ca2+ could affect pathological process is beyond the scope of this review, here we briefly present data suggesting their roles.
Alzheimer disease is a progressive neurodegenerative disease that can involve changes brain PLA2 and PUFA metabolism, with evidence for marked disturbances in brain Ca2+ homeostasis including excess Ca2+ release from the ER [163–165]. AA metabolism was shown to be increased in brains of Alzheimer disease patients using positron emission tomography, presumably in relation to neuroinflammation and activation of cPLA2 and sPLA2 via astrocytic cytokine receptors [166, 167] [168–170], whose immunoreactivity have both been reported to be increased in the postmortem Alzheimer brain [50, 170]. cPLA2 can be activated by entry of extracellular Ca2+ into cells through ionotropic NMDA receptors , and NMDA binding sites were decreased in the postmortem Alzheimer disease brain . cPLA2 mediated AA release can be increased by the β-amyloid peptide that accumulates in the Alzheimer disease brain, probably via mediation of NMDA receptors . Additionally, a low plasma DHA level has been associated with Alzheimer disease , but controlled supplementation studies have not been performed. β-amyloid can induce membrane-associated oxidative stress or form an oligomeric pore in the membrane , which could affect cPLA2 activity. DHA may be beneficial in Alzheimer disease by decreasing β-amyloid release .
Depolarization caused by energy failure in cerebral ischemia will lead to opening of voltage-gated Ca2+ channels in the membrane and excessive release of neurotransmitters , including glutamate. Glutamate activation of NMDA receptors normally is limited by magnesium blocking the channel, but depolarization releases magnesium and the receptor can then be opened to Ca2+ by the excessive glutamate . In ischemia, a sustained depolarization and excess glutamate can maintain the NMDA channel open and load Ca2+ into the cell , thereby activating Ca2+-sensitive enzymes including cPLA2 [178–181], and causing inflammatory mediator production [178, 182]. Hypoxia was shown to release both AA and DHA in rat brain, at a ratio of 3.6 to 1 . In ischemia, neuroprotectin D1 and DHA were protective [183–185]. DHA can block currents of L-type of calcium channels, and inhibit AA induced prostaglandin production .
Depression has been proposed to be related to NMDA receptor overactivation [186–188], with resultant neuronal damage . Thus, NMDA receptor antagonists induce an antidepressant effect in animal models [190–193] and in humans , and classical antidepressants can regulate NMDA receptor function . Neuroinflammation likely is involved in depression . Decreased plasma DHA levels were found in depressed individuals with coronary problems , but n-3 PUFA supplementation in depressed patients produced contradictory results [196, 197].
Neurodegeneration associated with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders, and includes patients with mutations in the PLA2G6 gene encoding iPLA2β . Children with PLA2G6 mutations show progressive cognitive and motor skill regression, with cerebellar ataxia and dystonia, as well as cerebellar cortical atrophy and gliosis. Mice with a targeted disruption of the iPLA2β gene show severe motor dysfunction, associated with widespread degeneration of brain axons and/or synapses, accompanied by the swollen axons and vacuoles .
cPLA2 and iPLA2 are important lipid regulatory enzymes that selectively release AA and DHA, respectively, from brain membrane phospholipids. The two PUFAs and their metabolites have many physiological effects and their relative rates and brain sites of release, controlled by the two enzymes and their concentrations in phospholipid, may help to fine-tune brain physiology and metabolism and when disrupted, lead to psychiatric and neurological disease. cPLA2 has been shown to depend on extracellular-derived Ca2+ in both in vitro and in vivo studies. Although Ca2+ was shown not to be necessary for iPLA2 activation in some in vitro studies, Ca2+ released from the intracellular stores of the ER can activate iPLA2 in cells, which suggests that activation can depend on Ca2+ in vivo. Neurotransmitters coupled to InsP3R activation or to CICR modulate iPLA2 activity by regulating intracellular Ca2+ stores. Further experiments are needed to elaborate the in vivo conditions under which this occurs.
We thank J. Bell, Dr. M. Basselin, Dr. J. Rao, Dr. M. Igarashi, Dr. F. Gao, Dr. J.Y. Park and the NIH Fellows Editorial Board for reviewing the manuscript. We also thank Kathy Benjamin for correcting the language of this manuscript. This study was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The authors have no conflict of interest.
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