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  • 1
    Electronic Resource
    Electronic Resource
    Calcium Binds Dynamin I and Inhibits Its GTPase Activity (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Synaptic vesicle recycling is a neuronal specialization of endocytosis that requires the GTPase activity of dynamin I and is triggered by membrane depolarization and Ca2+ entry. To establish the relationship between dynamin I GTPase activity and Ca2+, we used purified dynamin I and analyzed its interaction with Ca2+ in vitro. We report that Ca2+ bound to dynamin I and this was abolished by deletion of dynamin's C-terminal tail. Phosphorylation of dynamin I by protein kinase C promoted formation of a dynamin I tetramer and increased Ca2+ binding to the protein. Moreover, Ca2+ inhibited dynamin I GTPase activity after stimulation by phosphorylation or by phospholipids but not after stimulation with a GST-SH3 fusion protein containing the SH3 domain of phosphoinositide 3-kinase. These results suggest that in resting nerve terminals, phosphorylation of dynamin I by protein kinase C converts it to a tetramer that functions as a Ca2+-sensing protein. By binding to Ca2+, dynamin I GTPase activity is specifically decreased, possibly to regulate synaptic vesicle recycling.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66052074.x
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  • 2
    Electronic Resource
    Electronic Resource
    Cyclic GMP-Dependent Protein Kinase Substrates in Rat Brain (1995)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 65 (1995), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Cyclic GMP (cGMP)-dependent protein kinase (PKG) has a limited substrate specificity, and only cerebellar G-substrate has been demonstrated in brain. In view of the physiological importance of cGMP and PKG in the nervous system, it is important to identify endogenous PKG substrates in rat brain. We devised a combination of ion-exchange and hydrophobic chromatographies to identify potential PKG substrates. Extracts from cytosol, peripheral membrane proteins, or a fraction enriched in Ca2+-sensitive lipid-binding proteins were partly purified and phosphorylated with purified PKG. Using whole extracts only a single specific PKG substrate—P34—was found. However, after chromatography we detected 〉40 distinct proteins that were phosphorylated by PKG to a much greater extent than by cyclic AMP-dependent protein kinase or protein kinase C. Four PKG substrates—P140, P65, P32, and P18—were detected in the cytosol. Six PKG substrates—P130, P85 (doublet), P58, P54, and P38—were enriched from the Ca2+-sensitive lipid-binding protein fraction. In peripheral membrane fractions 〉30 relatively specific PKG substrates were enriched after chromatography, especially P130, P94, P58, P52, P45, P40, P36, P34, P28, P26, P24, and P20. These results indicate that brain is not lacking in PKG substrates and show that many are apparently quite specific substrates for this enzyme. The identification of some of these novel PKG substrates will facilitate understanding the role of cGMP signaling in the brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1995.65020595.x
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  • 3
    Electronic Resource
    Electronic Resource
    Dephosphorylation of Synaptosomal Proteins P96 and P139 Is Regulated by Both Depolarization and Calcium, but Not by a Rise in Cytosolic Calcium Alone (1987)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 48 (1987), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Depolarization of intact synaptosomes activates calcium channels, leads to an influx of calcium, and increases the phosphorylation of several neuronal proteins. In contrast, there are two synaptosomal phosphoproteins labeled in intact synaptosomes with 32P1, termed P96 and P 139, which appear to be dephosphorylated following depolarization. Within intact synaptosomes P96 was found in the cytosol whereas P 139 was present largely in membrane fractions. Depolarization-stimulated dephosphorylation was fully reversible and continued for up to five cycles of depolarization/repolarization, suggesting a physiological role for the phenomenon. The basal phosphorylation of these proteins was at least partly regulated by cyclic AMP, since dibutyryl cyclic AMP produced small but significant increases in P96 and P 139 labeling, even in the presence of fluphenazine at concentrations that inhibited calcium-stimulated protein kinases. Depolarization-dependent dephosphorylation was independent of a rise in intracellular calcium, since agents such as guanidine and low concentrations of A23187, which increase intracellular calcium without activating the calcium channel, did not initiate P96 or P 139 dephosphorylation. These agàents did sustain increases in the phosphorylation of a number of other proteins including synapsin I and protein III. The results suggest that the phosphorylation of these two synaptosomal proteins is intimately linked to the membrane potential and that their dephosphorylation is dependent on both the mechanism of calcium entry and calcium itself, rather than simply on a rise in intracellular free calcium.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1987.tb13146.x
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  • 4
    Electronic Resource
    Electronic Resource
    Septin 3 (G-septin) is a developmentally regulated phosphoprotein enriched in presynaptic nerve terminals (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 91 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The septins are GTPase enzymes with multiple roles in cytokinesis, cell polarity or exocytosis. The proteins from the mammalian septin genes are called Sept1–10. Most are expressed in multiple tissues, but the mRNA for Sept5 (CDCrel-1) and Sept3 (G-septin) appear to be primarily expressed in brain. Sept3 is phosphorylated by cGMP-dependent protein kinase I (PKG-I) and the cGMP/PKG pathway is involved in presynaptic plasticity. Therefore to determine whether Sept3 specifically associates with neurones and nerve terminals we investigated its distribution in rat brain and neuronal cultures. Sept3 protein was detected only in brain by immunoblot, but not in 12 other tissues examined. Levels were high in all adult brain regions, and reduced in those enriched in white matter. Expression was developmentally regulated, being absent in the early embryo, low in late embryonic rat brain and increasing after birth. Like dynamin I, Sept3 was specifically enriched in synaptosomes compared with whole brain, and was only found in a peripheral membrane extract and not in the soluble or membrane extracts. Sept3 was particularly abundant in mossy fibre nerve terminals in the hippocampus. In primary cultured hippocampal neurones Sept3 immunoreactivity was punctate in neurites and predominantly localized to presynaptic terminals, strongly colocalizing with synaptophysin and dynamin I. The specific nerve terminal localization was confirmed by immunogold electron microscopy. Together this shows that Sept3 is a neurone-specific protein highly enriched in nerve terminals which supports a secretory role in synaptic vesicle recycling.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02755.x
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  • 5
    Electronic Resource
    Electronic Resource
    Protein phosphorylation is required for endocytosis in nerve terminals: potential role for the dephosphins dynamin I and synaptojanin, but not AP180 or amphiphysin (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 76 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Dynamin I and at least five other nerve terminal proteins, amphiphysins I and II, synaptojanin, epsin and eps15 (collectively called dephosphins), are coordinately dephosphorylated by calcineurin during endocytosis of synaptic vesicles. Here we have identified a new dephosphin, the essential endocytic protein AP180. Blocking dephosphorylation of the dephosphins is known to inhibit endocytosis, but the role of phosphorylation has not been determined. We show that the protein kinase C (PKC) antagonists Ro 31-8220 and Go 7874 block the rephosphorylation of dynamin I and synaptojanin that occurs during recovery from an initial depolarizing stimulus (S1). The rephosphorylation of AP180 and amphiphysins 1 and 2, however, were unaffected by Ro 31-8220. Although these dephosphins share a single phosphatase, different protein kinases phosphorylated them after nerve terminal stimulation. The inhibitors were used to selectively examine the role of dynamin I and/or synaptojanin phosphorylation in endocytosis. Ro 31-8220 and Go 7874 did not block the initial S1 cycle of endocytosis, but strongly inhibited endocytosis following a second stimulus (S2). Therefore, phosphorylation of a subset of dephosphins, which includes dynamin I and synaptojanin, is required for the next round of stimulated synaptic vesicle retrieval.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00049.x
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  • 6
    Electronic Resource
    Electronic Resource
    Two Mechanisms of Synaptic Vesicle Recycling in Rat Brain Nerve Terminals (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 75 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: KCl and 4-aminopyridine (4-AP) evoke glutamate release from rat brain cortical nerve terminals by voltage clamping or by Na+ channel-generated repetitive action potentials, respectively. Stimulation by 4-AP but not KCl is largely mediated by protein kinase C (PKC). To determine whether KCl and 4-AP utilise the same mechanism to release glutamate, we correlated glutamate release with release of the hydrophobic synaptic vesicle (SV) marker FM2-10. A strong correlation was observed for increasing concentrations of KCl and after application of phorbol 12-myristate 13-acetate (PMA) or staurosporine. The parallel increase in exocytosis measured by two approaches suggested it occurred by a PKC-independent mechanism involving complete fusion of SVs with the plasma membrane. At low concentrations of 4-AP, alone or with staurosporine, glutamate and FM2-10 release also correlated. However, higher concentrations of 4-AP or of 4-AP plus PMA greatly increased glutamate release but did not further increase FM2-10 release. This divergence suggests that 4-AP recruits an additional mechanism of release during strong stimulation that is PKC dependent and is superimposed upon the first mechanism. This second mechanism is characteristic of kiss-and-run, which is not detectable by styryl dyes. Our data suggest that glutamate release in nerve terminals occurs via two mechanisms: (1) complete SV fusion, which is PKC independent; and (2) a kiss-and-run-like mechanism, which is PKC dependent. Recruitment of a second release mechanism may be a widespread means to facilitate neurotransmitter release in central neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0751645.x
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  • 7
    Electronic Resource
    Electronic Resource
    Cyclic GMP-Dependent Protein Kinase and Cellular Signaling in the Nervous System (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Nitric oxide (NO) and natriuretic peptide hormones play key roles in a surprising number of neuronal functions, including learning and memory. Most data suggest that they exert converging actions by elevation of intracellular cyclic GMP (cGMP) levels through activation of soluble and particulate guanylyl cyclases. However, cGMP is only the starting point for multiple signaling cascades, which are now beginning to be defined. A primary action of elevated cGMP levels is the stimulation of cGMP-dependent protein kinase (PKG), the major intracellular receptor protein for cGMP, which phosphorylates substrate proteins to exert its actions. It has become increasingly clear that PKG mediates some of the neuronal effects of cGMP, but how is not yet clear. One clear illustration of this pathway has been reported in striatonigral nerve terminals, where NO mediates phosphorylation of the protein phosphatase regulator dopamine- and cyclic AMP-regulated phosphoprotein having a molecular mass of 32,000 (DARPP-32) by PKG. There are remarkably few PKG substrates in brain whose identities are known. A survey of these proteins and those known from other tissues that might also be found in the nervous system reveals the key molecular sites where cGMP and PKG signaling is likely to be regulating neural function. These potential substrates are critically placed to have profound effects on the protein phosphorylation network through regulation of protein phosphatases, intracellular calcium levels, and the function of many ion channels and neurotransmitter receptors. The brain also contains a rich diversity of specific PKG substrates whose identities are not yet known. Their future identification will provide exciting new leads that will permit better understanding of the role of PKG signaling in both basic and higher orders of brain function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68020443.x
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  • 8
    Electronic Resource
    Electronic Resource
    Atrial Natriuretic Peptide, Cyclic GMP Analogues and Modulation of Guanylyl Cyclase do not Alter Stimulated POMC Peptide Release From Perifused Rat or Sheep Corticotrophs (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neuroendocrinology 9 (1997), S. 0 
    Details
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) are two potent stimulators for secretion of proopiomelanocortin (POMC)-derived hormones, from corticotrophs. CRH also stimulates POMC synthesis. Atrial natriuretic peptide (ANP) has been reported to inhibit POMC peptide release and is thought to act through cGMP signalling pathways. A multicolumn cell perifusion system was used to investigate the role of cGMP signalling pathways in CRH- and AVP-stimulated POMC peptide release from primary cultures of ovine or rat anterior pituitary cells. The CRH and/or AVP stimulations were applied at 30 min intervals as 5 min pulses, and the various treatments were infused over a period of 50 min, overlapping with 2 of the stimulations. ANP (10 nM) had no effect on β-endorphin (βEP) release from ovine cells, stimulated by 0.5 nM CRH and 5 nM AVP together, or 5 nM CRH and 50 nM AVP separately. Rat anterior pituitary cells were stimulated with 0.05 nM CRH/0.5 nM AVP or 0.5 nM CRH/5 nM AVP and treated with 1 nM or 10 nM ANP, respectively. No inhibition of ACTH or βEP was observed. Similarly, the nitric oxide donors molsidomine (100 μM), SIN-1 (100 μM) and NaNO2 (100 μM) did not inhibit βEP release stimulated by 0.5 nM CRH/5 nM AVP in ovine cells. The cGMP analogues 8-bromo-cGMP (10 μM and 100 μM) and dibutyryl cGMP (100 μM) also had no effect on βEP and ACTH release from ovine or rat anterior pituitary cells. Dexamethasone (8 μM), a synthetic glucocorticoid known to block POMC synthesis and secretion of βEP and ACTH by a distinct mechanism, was used as a control and suppressed CRH/AVP-stimulated βEP secretion from ovine anterior pituitary cells. These results contrast with some previous studies and demonstrate that the cGMP signalling pathway in sheep or rat anterior pituitary cells does not directly inhibit secretion of POMC-derived hormones from corticotrophs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1365-2826.1997.00665.x
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  • 9
    Electronic Resource
    Electronic Resource
    Depolarisation-Dependent Protein Phosphorylation in Rat Cortical Synaptosomes Is Inhibited by Fluphenazine at a Step After Calcium Entry (1984)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 43 (1984), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The sequence of molecular events linking depolarisation-dependent calcium influx to calcium-stimulated protein phosphorylation is unknown. In this study the effect of the neuroleptic drug fluphenazine on depolarisation-dependent protein phosphorylation was investigated using an intact postmitochondrial pellet isolated from rat cerebral cortex. Fluphenazine, in a dose-dependent manner, completely inhibited the increases in protein phosphorylation observed previously. The concentration of fluphenazine required for 50% inhibition varied for different phosphoproteins but for synapsin I was 123 μM. Other neuroleptics produced effects similar to fluphenazine with their order of potency being thioridazine 〉 haloperidol 〉 trifluoperazine 〉 fluphenazine 〉 chlorpromazine. Fluphenazine also increased the phosphorylation of proteins in nondepolarised controls at concentrations of 20 and 60 μM. The inhibition of depolarisation-dependent phosphorylation was apparently not due to a loss of synaptosomal integrity or viability, a decrease in calcium uptake, a change in substrate availability, or to a change in protein phosphatase activity. The data are most consistent with an inhibition of protein kinase activity by blockade of calmodulin or phospholipid activation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1984.tb12785.x
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  • 10
    Electronic Resource
    Electronic Resource
    Depolarisation-Dependent Protein Phosphorylation and Dephosphorylation in Rat Cortical Synaptosomes Is Modulated by Calcium (1985)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 44 (1985), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The effect of calcium on protein phosphorylation was investigated using intact synaptosomes isolated from rat cerebral cortex and prelabelled with 32Pi. For nondepolarised synaptosomes a group of calcium-sensitive phosphoproteins were maximally labelled in the presence of 0.1 mM calcium. The phosphorylation of these proteins was slightly decreased in the presence of strontium and absent in the presence of barium, consistent with the decreased ability of these cations to activate calcium-stimulated protein kinases. Addition of calcium alone to synaptosomes prelabelled in its absence increased phosphorylation of a number of proteins. On depolarisation in the presence of calcium certain of the calcium-sensitive phosphoproteins were further increased in labelling above nondepolarised levels. These increases were maximal and most sustained after prelabelling at 0.1 mM calcium. On prolonged depolarisation at this calcium concentration a slow decrease in labelling was observed for most phosphoproteins, whereas a greater rate and extent of decrease occurred at higher calcium concentrations. At 2.5 mM calcium a rapid and then a subsequent slow dephosphorylation was observed, indicating two distinct phases of dephosphorylation. Of all the phosphoproteins normally stimulated by depolarisation, only phosphoprotein 59 did not exhibit the rapid phase of dephosphorylation at high calcium concentrations. Replacing calcium with strontium markedly decreased the extent of change observed on depolarisation whereas barium decreased phosphorylation changes even further. Taken together these data suggest that an influx of calcium into synaptosomes initially activates protein phosphorylation, but as the levels of intrasynaptosomal calcium rise protein dephosphorylation predominates. Other phosphoproteins were dephosphorylated immediately on depolarisation in the presence of calcium. The fine control of protein phosphorylation levels exerted by calcium supports the idea that the synaptosomal phosphoproteins could play a role in modulating events such as neurotransmitter release in the nerve terminal.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1985.tb05422.x
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