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A lipid kinase controls the maintenance of dendritic spines.

Frere SG, Di Paolo G - EMBO J. (2009)

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.

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Dendritic spines are tiny membranous protrusions from neuronal dendrites that receive inputs from other neurons' nerve terminals and are believed to provide an anatomical substrate for memory storage and synaptic transmission... A new study in this issue suggests that a diacylglycerol (DAG) kinase isoform interacts with a major scaffolding protein of the spines, PSD-95, and regulates the dynamics of these structures as well as synaptic transmission... At neuronal synapses, mounting evidence implicates lipids, such as phosphoinositides, as critical regulators of synaptic transmission... These structures are dynamic actin-rich protrusions of neuronal dendrites that are characteristic of excitatory neurons and receive inputs from other neurons' presynaptic terminals... The decreased spine density in pyramidal neurons from DGKζ knock out hippocampi correlated with functional deficits in AMPAR-mediated synaptic transmission... This study by Kim et al also raises the need for the identification of the molecular effectors of DAG (and potentially PA) that are involved in the regulation of dendritic spine maintenance... Surprisingly, the PKC pathway does not appear to be implicated... Members of the chimaerin family are likely DAG effectors at spines, based on the ability of these C1 domain-containing proteins to regulate actin dynamics through their RacGAP domain... Accordingly, α1-chimaerin loss of function leads to an overgrowth of dendritic spines, a phenotype reminiscent of that observed upon DGK overexpression... Other potential effectors of DAG and PA are discussed in Kim et al... Finally, the findings reported by the authors may be relevant for brain disorders that are associated with synaptic dysfunction and cognitive deficits... For instance, amyloid beta, a major synaptotoxic agent in Alzheimer's disease, has been shown to decrease spine density in various instances, which, along with recent studies indicating that this cytotoxic peptide activates the PLC pathway and DAG production, may be related to the phenomena occurring in DGKζ-deficient synapses.

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Hypothetical scheme of the role of DGKζ in the regulation dendritic spine morphology. Based on Kim et al (this issue of EMBO J), the recruitment of DGKζ to the postsynaptic density of dendritic spines occurs through an interaction of its COOH-terminus (PB, PDZ domain-binding) with the PDZ domains of PSD-95 and related family members. These proteins are anchored to the membrane through a lipid modification and localize to the PSD through a variety of direct or indirect interactions with neurotransmitter receptors. PLC activation downstream of NMDAR or group I mGluR activation leads to hydrolysis of PIP2 to DAG and IP3. DAG can be further converted to PA by the kinase domain of DGKζ, following recruitment of the lipid kinase to DAG-rich membranes through its C1 domain. In the absence of DGKζ, accumulation of DAG and increased recruitment of DAG effectors are believed to cause spine loss. Alternatively, this phenotype can result from reduced production of PA and recruitment of PA effectors. GK, guanylate kinase-like domain.
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f1: Hypothetical scheme of the role of DGKζ in the regulation dendritic spine morphology. Based on Kim et al (this issue of EMBO J), the recruitment of DGKζ to the postsynaptic density of dendritic spines occurs through an interaction of its COOH-terminus (PB, PDZ domain-binding) with the PDZ domains of PSD-95 and related family members. These proteins are anchored to the membrane through a lipid modification and localize to the PSD through a variety of direct or indirect interactions with neurotransmitter receptors. PLC activation downstream of NMDAR or group I mGluR activation leads to hydrolysis of PIP2 to DAG and IP3. DAG can be further converted to PA by the kinase domain of DGKζ, following recruitment of the lipid kinase to DAG-rich membranes through its C1 domain. In the absence of DGKζ, accumulation of DAG and increased recruitment of DAG effectors are believed to cause spine loss. Alternatively, this phenotype can result from reduced production of PA and recruitment of PA effectors. GK, guanylate kinase-like domain.

Mentions: Intracellular signalling lipids are key regulators of cell physiology. At neuronal synapses, mounting evidence implicates lipids, such as phosphoinositides, as critical regulators of synaptic transmission (Di Paolo and De Camilli, 2006). One of the best characterized reactions in phosphoinositide-based signalling is the hydrolysis of PIP2 to DAG and IP3 by PLC (Di Paolo and De Camilli, 2006) (Figure 1). Whereas soluble IP3 mediates the release of Ca2+ from intracellular stores, membrane-bound DAG stimulates PKC (Di Paolo and De Camilli, 2006). In addition, DAG regulates a variety of proteins harbouring PKC domain 1 (i.e. C1 domains), such as members of the Munc13 (i.e. factors involved in vesicle ‘priming'), chimaerin (i.e. RacGAP) and DAG kinase (DGK) families (Brose and Rosenmund, 2002; Buttery et al, 2006; Topham, 2006). On the basis of its pivotal signalling role and, particularly, its capacity to amplify signals, DAG must be tightly regulated. One of the mechanisms involved in the control of DAG levels is the DGK pathway, which converts DAG to phosphatidic acid (PA), another bioactive signalling lipid (Topham, 2006). This conversion has two functional implications—the termination of DAG signalling and the initiation of PA signalling. Consistent with the daunting complexity of DAG/PA actions, multiple DGK-encoding genes are present in the genome of higher eurakyotes (Topham, 2006). In the fly phototransduction cascade, a DGK member (RdgA) mediates light response inactivation (Hardie, 2007). In the worm, mutations in DGK-1 modulate presynaptic release of acetylcholine, likely reflecting the effects of DAG accumulation on vesicle priming factor, Unc13 (Nurrish et al, 1999). However, evidence for synaptic roles for mammalian DGKs has been scant before the study by Kim et al published in this issue of EMBO J.


A lipid kinase controls the maintenance of dendritic spines.

Frere SG, Di Paolo G - EMBO J. (2009)

Hypothetical scheme of the role of DGKζ in the regulation dendritic spine morphology. Based on Kim et al (this issue of EMBO J), the recruitment of DGKζ to the postsynaptic density of dendritic spines occurs through an interaction of its COOH-terminus (PB, PDZ domain-binding) with the PDZ domains of PSD-95 and related family members. These proteins are anchored to the membrane through a lipid modification and localize to the PSD through a variety of direct or indirect interactions with neurotransmitter receptors. PLC activation downstream of NMDAR or group I mGluR activation leads to hydrolysis of PIP2 to DAG and IP3. DAG can be further converted to PA by the kinase domain of DGKζ, following recruitment of the lipid kinase to DAG-rich membranes through its C1 domain. In the absence of DGKζ, accumulation of DAG and increased recruitment of DAG effectors are believed to cause spine loss. Alternatively, this phenotype can result from reduced production of PA and recruitment of PA effectors. GK, guanylate kinase-like domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2683711&req=5

f1: Hypothetical scheme of the role of DGKζ in the regulation dendritic spine morphology. Based on Kim et al (this issue of EMBO J), the recruitment of DGKζ to the postsynaptic density of dendritic spines occurs through an interaction of its COOH-terminus (PB, PDZ domain-binding) with the PDZ domains of PSD-95 and related family members. These proteins are anchored to the membrane through a lipid modification and localize to the PSD through a variety of direct or indirect interactions with neurotransmitter receptors. PLC activation downstream of NMDAR or group I mGluR activation leads to hydrolysis of PIP2 to DAG and IP3. DAG can be further converted to PA by the kinase domain of DGKζ, following recruitment of the lipid kinase to DAG-rich membranes through its C1 domain. In the absence of DGKζ, accumulation of DAG and increased recruitment of DAG effectors are believed to cause spine loss. Alternatively, this phenotype can result from reduced production of PA and recruitment of PA effectors. GK, guanylate kinase-like domain.
Mentions: Intracellular signalling lipids are key regulators of cell physiology. At neuronal synapses, mounting evidence implicates lipids, such as phosphoinositides, as critical regulators of synaptic transmission (Di Paolo and De Camilli, 2006). One of the best characterized reactions in phosphoinositide-based signalling is the hydrolysis of PIP2 to DAG and IP3 by PLC (Di Paolo and De Camilli, 2006) (Figure 1). Whereas soluble IP3 mediates the release of Ca2+ from intracellular stores, membrane-bound DAG stimulates PKC (Di Paolo and De Camilli, 2006). In addition, DAG regulates a variety of proteins harbouring PKC domain 1 (i.e. C1 domains), such as members of the Munc13 (i.e. factors involved in vesicle ‘priming'), chimaerin (i.e. RacGAP) and DAG kinase (DGK) families (Brose and Rosenmund, 2002; Buttery et al, 2006; Topham, 2006). On the basis of its pivotal signalling role and, particularly, its capacity to amplify signals, DAG must be tightly regulated. One of the mechanisms involved in the control of DAG levels is the DGK pathway, which converts DAG to phosphatidic acid (PA), another bioactive signalling lipid (Topham, 2006). This conversion has two functional implications—the termination of DAG signalling and the initiation of PA signalling. Consistent with the daunting complexity of DAG/PA actions, multiple DGK-encoding genes are present in the genome of higher eurakyotes (Topham, 2006). In the fly phototransduction cascade, a DGK member (RdgA) mediates light response inactivation (Hardie, 2007). In the worm, mutations in DGK-1 modulate presynaptic release of acetylcholine, likely reflecting the effects of DAG accumulation on vesicle priming factor, Unc13 (Nurrish et al, 1999). However, evidence for synaptic roles for mammalian DGKs has been scant before the study by Kim et al published in this issue of EMBO J.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Dendritic spines are tiny membranous protrusions from neuronal dendrites that receive inputs from other neurons' nerve terminals and are believed to provide an anatomical substrate for memory storage and synaptic transmission... A new study in this issue suggests that a diacylglycerol (DAG) kinase isoform interacts with a major scaffolding protein of the spines, PSD-95, and regulates the dynamics of these structures as well as synaptic transmission... At neuronal synapses, mounting evidence implicates lipids, such as phosphoinositides, as critical regulators of synaptic transmission... These structures are dynamic actin-rich protrusions of neuronal dendrites that are characteristic of excitatory neurons and receive inputs from other neurons' presynaptic terminals... The decreased spine density in pyramidal neurons from DGKζ knock out hippocampi correlated with functional deficits in AMPAR-mediated synaptic transmission... This study by Kim et al also raises the need for the identification of the molecular effectors of DAG (and potentially PA) that are involved in the regulation of dendritic spine maintenance... Surprisingly, the PKC pathway does not appear to be implicated... Members of the chimaerin family are likely DAG effectors at spines, based on the ability of these C1 domain-containing proteins to regulate actin dynamics through their RacGAP domain... Accordingly, α1-chimaerin loss of function leads to an overgrowth of dendritic spines, a phenotype reminiscent of that observed upon DGK overexpression... Other potential effectors of DAG and PA are discussed in Kim et al... Finally, the findings reported by the authors may be relevant for brain disorders that are associated with synaptic dysfunction and cognitive deficits... For instance, amyloid beta, a major synaptotoxic agent in Alzheimer's disease, has been shown to decrease spine density in various instances, which, along with recent studies indicating that this cytotoxic peptide activates the PLC pathway and DAG production, may be related to the phenomena occurring in DGKζ-deficient synapses.

Show MeSH
Related in: MedlinePlus