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Complement Cascade Mediates Synapse Remodeling
This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.
The importance of synapse elimination during nervous system development has been recognized for several decades. Growing evidence suggest that the immune and nervous system make different use of some of the same molecular machinery. Postnatally, the number of neuromuscular junctions decreases as functionally redundant neural connections are eliminated. This phenomenon coincides with the maturation of the remaining neuromuscular junctions and leads to the development of a more mature, optimally innervated state.
Evidence from a number of sources has accumulated to suggest that thrombin (f2, yellow node in the center) and PAR-1 (orange) play an important role in the activity-dependent polyneuronal synapse elimination (ADPSE) that occurs during the development of the optimally innervated state of mature skeletal muscle. Evidence of ADPSE has been obtained from studies on the expression of prothrombin, PAR-1 and the thrombin inhibitor protease nexin-1 (PN-1) during postnatal mouse muscle development. The current model of the role of PAR-1 and thrombin in ADPSE is that postnatally in the absence of PN-1, the local generation and activation of prothrombin by cholinergically stimulated muscle fibers results in the activation of PAR-1 on the postsynaptic membrane. Activation of PAR-1 results in increased protein kinase C (PKC) activity, leading to disorganization and destabilization of the postsynaptic membrane and ultimately to elimination of redundant neuronal connections.
It has been demonstrated that a thrombin receptor-activating peptide (TRAP), SFLLRNPNDKYEPF, produces a decrement of synapse strength. Both TRAP and electrically evoked synapse decrement are prevented by the specific PKC blocker calphostin C; the TRAP-evoked synapse decrement is unaffected by a specific protein kinase A blocker, H-89. Thus, it has been proposed that muscle activity, thrombin release, as well as thrombin receptor and PKC activation are initial steps in activity-dependent synapse reduction.
An alternative role is played by tissue transglutaminase (Tgase/tTG), a globular monomeric protein having a Mr of about 70 kDa. tTG is expressed in muscle and participates in neuromuscular development, including the formation and stabilization of the synapse. It may do so by binding serpins, such as the plasminogen activator inhibitors (PAIs) or protease nexin I (PNI), or other molecules involved in plasminogen metabolism such as midkine.
Evidence from a number of sources has accumulated to suggest that thrombin (f2, yellow node in the center) and PAR-1 (orange) play an important role in the activity-dependent polyneuronal synapse elimination (ADPSE) that occurs during the development of the optimally innervated state of mature skeletal muscle. Evidence of ADPSE has been obtained from studies on the expression of prothrombin, PAR-1 and the thrombin inhibitor protease nexin-1 (PN-1) during postnatal mouse muscle development. The current model of the role of PAR-1 and thrombin in ADPSE is that postnatally in the absence of PN-1, the local generation and activation of prothrombin by cholinergically stimulated muscle fibers results in the activation of PAR-1 on the postsynaptic membrane. Activation of PAR-1 results in increased protein kinase C (PKC) activity, leading to disorganization and destabilization of the postsynaptic membrane and ultimately to elimination of redundant neuronal connections.
It has been demonstrated that a thrombin receptor-activating peptide (TRAP), SFLLRNPNDKYEPF, produces a decrement of synapse strength. Both TRAP and electrically evoked synapse decrement are prevented by the specific PKC blocker calphostin C; the TRAP-evoked synapse decrement is unaffected by a specific protein kinase A blocker, H-89. Thus, it has been proposed that muscle activity, thrombin release, as well as thrombin receptor and PKC activation are initial steps in activity-dependent synapse reduction.
An alternative role is played by tissue transglutaminase (Tgase/tTG), a globular monomeric protein having a Mr of about 70 kDa. tTG is expressed in muscle and participates in neuromuscular development, including the formation and stabilization of the synapse. It may do so by binding serpins, such as the plasminogen activator inhibitors (PAIs) or protease nexin I (PNI), or other molecules involved in plasminogen metabolism such as midkine.
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