Control of the Postsynaptic Membrane Viscosity

Renner, Marianne; Choquet, Daniel; Triller, Antoine

doi:10.1523/jneurosci.4445-08.2009

Cited by 139 publications

(169 citation statements)

References 55 publications

(95 reference statements)

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“…enrichment in cholesterol, glycosphingolipids, sphingomyelin, and other saturated fatty acid-containing lipids (GM 1 gangliosides, palmitic acid)) (39). Other evidence supports a role for free cholesterol and membrane/lipid rafts in formation of neuronal synapses and in the signaling and protection of neurons (7,9,12,40,41). Moreover, as an essential component of rafts, cholesterol and changes in the cellular content of cholesterol can affect Cav expression (42,43).…”

Section: Discussionmentioning

confidence: 95%

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

Head

Finley

et al. 2011

Journal of Biological Chemistry

113

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Decreased expression of prosurvival and progrowth-stimulatory pathways, in addition to an environment that inhibits neuronal growth, contribute to the limited regenerative capacity in the central nervous system following injury or neurodegeneration. Membrane/lipid rafts, plasmalemmal microdomains enriched in cholesterol, sphingolipids, and the protein caveolin (Cav) are essential for synaptic development/stabilization and neuronal signaling. Cav-1 concentrates glutamate and neurotrophin receptors and prosurvival kinases and regulates cAMP formation. Here, we show that primary neurons that express a synapsin-driven Cav-1 vector (SynCav1) have increased raft formation, neurotransmitter and neurotrophin receptor expression, NMDA-and BDNF-mediated prosurvival kinase activation, agonist-stimulated cAMP formation, and dendritic growth. Moreover, expression of SynCav1 in Cav-1 KO neurons restores NMDA-and BDNF-mediated signaling and enhances dendritic growth. The enhanced dendritic growth occurred even in the presence of inhibitory cytokines (TNF␣, IL-1␤) and myelin-associated glycoproteins (MAG, Nogo). Targeting of Cav-1 to neurons thus enhances prosurvival and progrowth signaling and may be a novel means to repair the injured and neurodegenerative brain.Multiple signaling pathways have been identified that promote growth and survival of neurons and thereby facilitate the formation of synaptic connections that are essential for learning, memory, and the development of the CNS (1-3). Neurotransmitter and neurotrophic receptors, non-receptor tyrosine kinases, and other signaling mediators aggregate to mold and shape postsynaptic densities to permit high-fidelity signal transduction and the regulation of neuronal function (4 -6). A major non-protein component of synapses is cholesterol, which can be a limiting factor in synapse development, synaptic activity, and transmitter release (7).Increasing evidence shows that membrane/lipid rafts, discrete regions of the plasma membrane enriched in cholesterol, glycosphingolipids, and sphingomyelin organize prosurvival and progrowth neuronal signaling pathways (8 -10), regulate cAMP formation (11), and are essential for synapse development, stabilization, and maintenance (7, 12). Caveolin (Cav), 2 a cholesterol binding protein and scaffolding protein found within membrane/lipid rafts (13), organizes and targets certain neuronal growth-promoting proteins, such as components of the neurotransmitter and neurotrophic receptor signaling pathways, to membrane/lipid rafts. These include NMDA receptors, AMPA receptors, Trk receptors, GPC receptors, and Src family kinases (9, 14 -16). These receptors and signaling molecules can enhance cAMP formation, an essential second messenger for promoting neuronal growth and dendritic arborization (17-21), and are found within membrane/lipid rafts in growth cones (6). In the setting of traumatic brain injury and neurodegenerative disorders, interventions that activate signaling pathways to stimulate cAMP production thus have the potential to improve...

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Section: Discussionmentioning

confidence: 95%

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

Head

Finley

et al. 2011

Journal of Biological Chemistry

113

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“…Single Particle Tracking and Analysis-Tracking and analysis of QDs has been well described recently (11,46). Briefly, QDs were detected by cross-correlating the image with a Gaussian model of the point spread function, and the diffusion parameters were calculated using custom software (13,47,48) using Matlab (The Mathworks Inc., Natick, MA).…”

Section: Methodsmentioning

confidence: 99%

Regulation of GABAA Receptor Dynamics by Interaction with Purinergic P2X2 Receptors

Shrivastava

Triller

Sieghart

et al. 2011

Journal of Biological Chemistry

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␥-Aminobutyric acid type A receptors (GABA A Rs) in the spinal cord are evolving as an important target for drug development against pain. Purinergic P2X 2 receptors (P2X 2 Rs) are also expressed in spinal cord neurons and are known to cross-talk with GABA A Rs. Here, we investigated a possible "dynamic" interaction between GABA A Rs and P2X 2 Rs using co-immunoprecipitation and fluorescence resonance energy transfer (FRET) studies in human embryonic kidney (HEK) 293 cells along with co-localization and single particle tracking studies in spinal cord neurons. Our results suggest that a significant proportion of P2X 2 Rs forms a transient complex with GABA A Rs inside the cell, thus stabilizing these receptors and using them for co-trafficking to the cell surface, where P2X 2 Rs and GABA A Rs are primarily located extra-synaptically. Furthermore, agonist-induced activation of P2X 2 Rs results in a Ca 2؉ -dependent as well as an apparently Ca 2؉ -independent increase in the mobility and an enhanced degradation of GABA A Rs, whereas P2X 2 Rs are stabilized and form larger clusters. Antagonist-induced blocking of P2XRs results in co-stabilization of this receptor complex at the cell surface. These results suggest a novel mechanism where association of P2X 2 Rs and GABA A Rs could be used for specific targeting to neuronal membranes, thus providing an extrasynaptic receptor reserve that could regulate the excitability of neurons. We further conclude that blocking the excitatory activity of excessively released ATP under diseased state by P2XR antagonists could simultaneously enhance synaptic inhibition mediated by GABA A Rs.GABA A Rs 2 are the major inhibitory transmitter receptors in the central nervous system and the site of action of benzodiazepines, barbiturates, neuroactive steroids, anesthetics, and convulsants. They are ligand-gated chloride channels composed of five subunits that can belong to different subunit classes. The majority of these receptors are composed of one ␥, two ␣, and two ␤ subunits (1-3). GABA A Rs are widely distributed in the brain (4, 5) and spinal cord (6). Clusters of these receptors can be found at inhibitory synapses mediating phasic inhibition but also at extrasynaptic locations where they are mediating tonic inhibition (7). Using single particle tracking (SPT), it has been demonstrated that most neurotransmitter receptors, including GABA A Rs, are exchanged between synaptic and extrasynaptic domains by lateral diffusion (8 -10). The lateral mobility of receptors can be modulated by interaction with scaffolding molecules such as gephyrin for GABA A (7, 11) and glycine receptors (12, 13). In addition, receptor insertion and removal are considered major determinants in the regulation of receptor number at the cell surface and the strength of GABAergic transmission (14, 15).The P2X receptor superfamily includes seven different subunits (P2X 1 -P2X 7 ) (16). P2X 2 subunits mainly form homotrimeric receptors but also assemble with P2X 3 subunits to form heterotrimeric P2X 2/3 receptors (P...

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“…In fact, it is being increasingly recognized that dysregulation of cholesterol metabolism and homeostasis may have a role in neurological diseases, such as Alzheimer's (Ledesma and Dotti, 2006;Gamba et al, 2012;Suzuki et al, 2013) and Huntington's (Valenza et al, 2005). On the other hand, cholesterol may influence multiple aspects of synaptic transmission (Pfrieger, 2003), both presynaptically, acting on neurotransmitter vesicle fusion (Deutsch and Kelly, 1981;Linetti et al, 2010;Smith et al, 2010;Mercer et al, 2012), and postsynaptically, altering neurotransmitter receptor diffusion (Renner et al, 2009) and endosomal dynamics (Hering et al, 2003;Hou et al, 2008). However, it remains to be established whether cholesterol metabolism is regulated by neuronal activity under physiological conditions, and particularly, what the molecular mechanisms are that link changes in cholesterol to the regulation of synaptic strength during plasticity.…”

Section: Ltp-triggered Cholesterol Redistribution Activates Cdc42 Andmentioning

confidence: 99%

LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery

Brachet¹,

Norwood²,

Brouwers³

et al. 2015

J Gen Physiol

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Control of the Postsynaptic Membrane Viscosity

Cited by 139 publications

References 55 publications

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

Regulation of GABAA Receptor Dynamics by Interaction with Purinergic P2X2 Receptors

LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery

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