Chapter Role of lysophospholipids in synaptic transmission LysoPI MBCD+lysoPI Normalized Capacitance(%) 1.08 1.04 * 1.00 0.96 30 Time(s) A LysoPI 0Ca+lysoPI Normalized Capacitance(%) 1.08 1.04 * 1.00 0.96 B 30 Time(s) Fig.2.5.3. Capacitance measurements. A: Treatment of cells with MBCD prior to addition of lysoPI resulted in attenuation of lysoPI induced exocytosis. B: Cells pre-treated with thapsigargin and recorded in zero external Ca2+ solution showed no induction of exocytosis after addition of lysoPI. *: significant difference (P < 0.05, analyzed by Student’s t-test). 5.3.3. Amperometry measurements (Fig. 2.5.4.) Infusion of lysoPI in the external solution resulted in an immediate increase in catecholamine release from PC-12 cells (132.7 ± 32.94 spikes) (Fig. 2.5.4A). This increase was markedly attenuated in cells that were pre-incubated with MBCD (3.5 ± 3.4 spikes) (Fig. 2.5.4B) or pre-treated with thapsigargin and recorded in zero Ca2+ conditions (2 ± 0.19 spikes) (Fig. 2.5.4C). These results 141 Chapter Role of lysophospholipids in synaptic transmission show that neurotransmitter release triggered by lysoPI was dependent on the integrity of cholesterol rich domains on the cell membrane and [Ca2+]i. 80 4pA 5s 60 -12 x10pA LysoPI, 10mM Ca2+ 40 20 0A 2+ LysoPI, , 20 10mM Ca40 MBCD treated 60 time (s) 80 100 120 B LysoPI, 0mM Ca2+, EGTA, thapsigargin Number of Events C D 190 150 110 70 30 -10 LysoPI MBCD+lysoPI 0Ca+lysoPI Fig.2.5.4. Amperometry measurements. A: infusion of lysoPI in the external solution resulted in an immediate increase in catecholamine release from PC-12 cells. B, C: this increase was completely abolished in cells that had been pre-incubated with MBCD (B) or Ca2+ free external solution containing the Ca2+ chelator EGTA and thapsigargin (C). D: summary results of experiments (A–C). Events are selected with spikes >2 pA for the first application of lysoPI. *: significant difference (P < 0.05, analyzed by Student’s t-test). 142 Chapter Role of lysophospholipids in synaptic transmission 5.3.4. Fura-2 measurements (Fig. 2.5.5.) LysoPI induced a sustained increase in [Ca2+]i in PC-12 cells of 1.06 ± 0.06 of normalized 340/380 ratio compared to the resting state. The increase in [Ca2+]i was markedly attenuated in cells that were pre-incubated with MBCD (1.0 ± 0.002 of normalized 340/380 ratio) or pre-treated with thapsigargin and recorded in zero Ca2+ conditions (1.0 ± 0.02 of normalized 340/380 ratio) (Fig. 2.5.5). LysoPI 0Ca+lysoPI MBCD+lysoPI Ethanol Normalized 340/380 1.10 1.06 1.02 0.98 400 800 Time(s) 1200 1600 Fig.2.5.5. Fura-2 imaging. LysoPI induced a sustained increase in [Ca2+]i in PC-12 cells. The lysoPI induced increase in [Ca2+]i was attenuated by pretreatment of cells with MBCD and by pre2+ incubation of cells with thapsigargin. No change in [Ca ]i concentration was detected after addition of ethanol (vehicle control). Arrow indicates time of addition of lysoPI. 143 Chapter Role of lysophospholipids in synaptic transmission 5.4. Discussion The present study demonstrated possible effects of lysophospholipids on exocytosis. An increase in vesicle fusion, indicating exocytosis, was observed in PC-12 cells after external infusion of the lysoPI, but not lysoPC or lysoPS by TIRFM. Similarly, external infusion of lysoPI, but not lysoPC or lysoPS induced significant increases in capacitance, or number of spikes detected by carbon fiber electrodes at amperometry, indicating exocytosis. Depletion of cholesterol by pre-incubation of cells with MBCD and depletion of Ca2+ by thapsigargin and incubation in zero external Ca2+ resulted in attenuation of lysoPI induced exocytosis, indicating that exocytosis was dependent on the integrity of lipid rafts and [Ca2+]i. Moreover, lysoPI induced a rise in [Ca2+]i suggesting that this could be the trigger for exocytosis. It is possible that lysoPI exerts it effects through binding to a lysoPI specific receptor on the cell membrane or by its physical properties on the cell membrane. A lysoPI specific receptor (GPR55) has been identified in the frontal cortex, striatum, hypothalamus, caudate putamen of the brain (Sawzdargo et al. 1999; Johns et al. 2007; Ryberg et al. 2007). In addition, lysoPI has ‘‘detergent like’’ actions and could affect the functions of ion channels or receptors on the cell membrane to cause an increase in [Ca2+]i concentration and exocytosis. The present results are consistent with previous studies which showed that lysoPI causes Ca2+ influx via store operated Ca2+ entry channels (Singaravelu et al. 2008). Moreover, lysoPI has been shown to mediate the release of insulin upon melittin (induced sPLA2) stimulation, a process which 144 Chapter Role of lysophospholipids in synaptic transmission exhibits the characteristics of physiologic exocytosis, i.e., it is reversible, saturable and does not influence subsequent islet functioning (Metz 1986). Besides lysoPI, phosphatidylinositol 4,5-bisphosphate (PtdIns (4,5)P2), a phosphoinositide found mainly in the plasma membrane also regulates exocytosis and synaptic transmission (Valtorta and Meldolesi 1994; Holz et al. 2000). PtdIns (4,5)P2 is thought to have multiple roles in exocytosis, including the establishment of secretory granule docking sites on the plasma membrane as well as participating in a step linked to fusion (Martin 2001). Moreover, glycosylphosphatidylinositol-anchored proteins in the lipid rafts of neurons are able to activate signaling pathways affecting exocytosis (Brown 2006). Previous studies have suggested a link between PLA2 and lysophospholipids in pancreatic secretion and mast cell degranulation. PLA2 and acyltransferase activities were identified in membranes associated with purified pancreatic zymogen granules. PLA2 activity was correlated to protein concentration and was Ca2+-dependent, consistent with a sPLA2 isoform. The intact zymogen granules and granule membranes demonstrated reacylating activity which was related to the concentration of lysophospholipid (Rubin et al. 1990). Similarly, PLA2 which prefers PI over PC as substrate has been detected in mast cell secretory granules. As with pancreatic zymogen granules, mast cell granules contain an active acylating system which rapidly reacylate lysoPI to form PI. These findings provide a basis for linking PLA2 activity and formation of lysophospholipids, to granule exocytosis (Chock et al. 1991). Besides lysoPI, lysoPS also provoked degranulation and histamine release in mast cells (Smith et al. 1979; Bigon et al. 145 Chapter Role of lysophospholipids in synaptic transmission 1980; Bruni et al. 1984) by enhancing stimulus-dependent Ca2+ ion influx through a specific membrane receptor (Inoue K et al. 1989). LysoPS did not cause exocytosis in PC-12 cells however. Another lysophospholipid, lysoPC also did not cause any exocytosis in PC-12 but it able to stimulate cell motility and releases pro-inflammatory cytokines. LysoPC modulates ion channel permeability in various brain preparations through at least three different mechanisms. By incorporating into neural membranes, it can perturb the orderly packing of phospholipid bilayers inducing alterations of the normal conformation of integral membrane proteins such as ion channels. Secondly, lysoPC can interact directly with ion channel proteins, and finally, lysoPC can modulate the ion channel by modulating signal transduction processes. Thus, in neurons, lysoPC produces prolonged hyperpolarization of K+ channels (Maingret et al. 2000). Under certain conditions, lysoPC also causes cell fusion. Thus, lysoPC may be involved in cell-cell and membrane-membrane interactions and neurotransmitter release (Farooqui and Horrocks 2006). The findings of a role of lysoPI in exocytosis may be important from the standpoint of the function of sPLA2 in neuroendocrine cells. Previous studies showed that external application of sPLA2-IIA (crotoxin B or purified human synovial sPLA2) to PC-12 cells and cultured rat hippocampal neurons resulted in an immediate increase in exocytosis and neurotransmitter release. EGTA and a specific inhibitor of sPLA2 activity, 12-epi-scalaradial, completely abolished the increase in neurotransmitter release, indicating that the effect of sPLA2 was dependent on Ca2+ and sPLA2 enzymatic activity (Wei et al. 2003). These 146 Chapter Role of lysophospholipids in synaptic transmission findings suggest that sPLA2 may have a role in exocytosis and neurotransmitter release in neuroendocrine cells and neurons. In recent findings (in chapter 4), it showed high levels of sPLA2-IIA expression in the brainstem and spinal cord. sPLA2-IIA protein was found in the brainstem, cervical, thoracic and lumbar spinal segments by Western blots. The enzyme was localized by immunohistochemistry to neuronal cell bodies and dendrites in the spinal trigeminal nucleus and the dorsal and ventral horns of the spinal cord. Electron microscopy of the spinal cord showed that sPLA2-IIA was localized in dendrites or dendritic spines that were postsynaptic to unlabeled axon terminals. sPLA2-IIA contains a strong secretory signal peptide, and it is probable that this isoform is actually secreted from neurons. In view of the effects of lysoPI on exocytosis mentioned above, it is possible that sPLA2-mediated effects on exocytosis could be partly due to the generation of lysoPI from hydrolysis of phosphatidylinositol which is located on the exofacial aspect of the cell membrane/or the inner leaflet of synaptic vesicles. It is postulated that secretion of sPLA2 from neurons and action on neuronal membranes to generate lysoPI from PI may play a role in neural transmission. If this is the case, a rapid reacylating enzyme such as lysoPI acyltransferase (Gijon et al. 2008) might also be expected to be present in CNS regions with high levels of sPLA2, and future studies are needed to evaluate this possibility. The contribution of another lysophospholipid, lysoPE to exocytosis could not be excluded, although these were not analyzed in this study due to 147 Chapter Role of lysophospholipids in synaptic transmission their insolubility in ethanol or aqueous solutions. Further work is necessary to elucidate possible sPLA2 and/or lysophospholipid mediated signaling in the CNS. 148 Section IV Conclusion SECTION IV CONCLUSION 149 Section IV Conclusion PLA2 isoforms play different roles in the CNS. Currently, there is still a lack of information regarding changes in PLA2 activity and expression after hyperalgesia and the role of PLA2 in the synaptic transmission. This study therefore, elucidated the role of PLA2, sPLA2 in particular, after orofacial pain. The changes in brain lipids indicating an increased PLA2 activity was accompanied by an increased expression of sPLA2-III. The study also demonstrated sPLA2-III function in neurotransmission using PC-12 cells. In elucidating the changes in brain lipids, it was observed that there was a decrease in phospholipids including PE and PI species, and an increase in corresponding lysophospholipids which included lysoPE, lysoPI and lysoPS in the CM after facial CA injection. These results indicated an elevated PLA2 activity and release of AA due to PLA2 enzymatic action on the phospholipids of the membrane. AA and its metabolites such as PEG2 and leukotrienes are shown to be biologically active and cause inflammation at nanomolar and micromolar concentrations (Saxena 2000; Mechiche et al. 2003; Wise 2006). These findings indicated increased CNS PLA2 activity, resulting in generation of metabolites that contribute to allodynia after peripheral inflammation. 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G (1997) Ca2+/phospholipid-binding and syntaxin-binding of native synaptotagmin I Life Sci 61: 711-721 Pruzanski W, Bogoch E, Wloch M, Vadas P (1991) The role of phospholipase A2 in the physiopathology of osteoarthritis J Rheumatol Suppl 27: 117-119 Pruzanski W, Lin KS, Vadas P (1995) Secretory phospholipase A2 in rheumatic diseases In: Glacer KB, Vadas P (eds) Phospholipase A2 in clinical inflammation... effects of snake venom phospholipases A2 Toxicon 27: 613-635 Kinsey GR, Blum JL, Covington MD, Cummings BS, McHowat J, Schnellmann RG (2008) Decreased iPLA2gamma expression induces lipid peroxidation and cell death and sensitizes cells to oxidant-induced apoptosis J Lipid Res 49 : 147 7- 148 7 Kinsey GR, McHowat J, Patrick KS, Schnellmann RG (2007) Role of Ca2+independent phospholipase A2gamma in Ca2+-induced... sPLA2 isozyme, sPLA2-IIA was also observed to be highly involved in nociception Using sPLA2-V as a comparison, the expression profiles of multiple sPLA2 isoforms with the strong secretory signals which included sPLA2-IB, -IIA, -IIC and –X, showed that both mRNA and protein expression of sPLA2-IIA were at high levels in the brainstem and spinal cord Moreover, sPLA2-IIA was also localized in the spinal... at the highest level in the brainstem and spinal cord It was localized in the spinal trigeminal nucleus, further supporting its role in the nociceptive pathway Functionally, sPLA2-III was observed to be involved in pain transmission as the external application of purified form of sPLA2-III, the bee venom, showed an increased membrane capacitance indicating exocytosis sPLA2-III induced exocytosis could... upon orofacial pain induced by facial CA injection Both sPLA2-III and sPLA2-IIA were observed to be the isozymes which play critical roles in the ascending pain pathway Moreover, evidence from this study has shown that sPLA2 could participate in pain transmission via the release of itself or through its enzymatic product, lysophospholipid This study therefore has provided a better understanding of this... Dubner R (eds) Orofacial pain : from basic science to clinical management ; the transfer of knowledge in pain research to education Quintessence Publishing Co, Inc, Illinois, pp 37 -46 Mattson MP, Chan SL (2003) Neuronal and glial calcium signaling in Alzheimer's disease Cell Calcium 34: 385-397 Maxfield FR, Tabas I (2005) Role of cholesterol and lipid organization in disease Nature 43 8: 612-621 Mayer... consistent with an increase in enzyme activity without any changes in enzyme protein expression Together, these findings showed enhanced PLA2 activity in the CM after inflammatory orofacial pain Further study on the expression profile of sPLA2-III in the CNS showed that the enzyme was expressed at the highest level in the medulla oblongata Both mRNA and protein expression of sPLA2-III in normal rat CNS... membrane-associated phospholipase A2 from rat spleen Its comparison with a cytosolic phospholipase A2 S-1 J Biol Chem 263: 5732-5738 Orr JW, Newton AC (1992) Interaction of protein kinase C with phosphatidylserine 1 Cooperativity in lipid binding Biochemistry 31: 46 61 -46 67 Orr SK, Bazinet RP (2008) The emerging role of docosahexaenoic acid in neuroinflammation Curr Opin Investig Drugs 9: 735- 743 Pal S, Sombati . exocytosis and neurotransmitter release in neuroendocrine cells and neurons. In recent findings (in chapter 4) , it showed high levels of sPLA 2 -IIA expression in the brainstem and spinal cord elucidated the role of PLA 2 , sPLA 2 in particular, after orofacial pain. The changes in brain lipids indicating an increased PLA 2 activity was accompanied by an increased expression of sPLA 2 -III in neurotransmission using PC-12 cells. In elucidating the changes in brain lipids, it was observed that there was a decrease in phospholipids including PE and PI species, and an increase in