Ras-Up, Rap-Down

Abstract

Changes in excitatory synaptic transmission in response to repetitive stimulation involve changes in the presence of AMPA-type glutamate receptors (AMPARs) in the synapses. AMPARs composed of subunits with long cytoplasmic tails are inserted into synapses during activity-induced synaptic enhancement; whereas AMPARs with short cytoplasmic tails are removed from synapses in response to activity-induced synaptic depression. Zhu et al. examined how the guanosine triphosphatases (GTPases) Ras and Rap influence hippocampal synaptic activity and the AMPARs in the synapses. In hippocampal slices that ectopically expressed consitutively active forms of Ras, there was enhancement of AMPAR-mediated synaptic activity. In hippocampal slices that ectopically expressed consitutively active forms of Rap, there was depression of AMPAR-mediated synaptic activity. Expression of dominant-negative Ras inhibited AMPAR activity, and expression of wild-type Ras enhanced AMPAR activity. Drugs that blocked the mitogen-activated and extracellular signal-regulated protein kinase (MEK) inhibited the Ras-mediated enhancement of AMPAR activity. Active Ras promoted the delivery of long forms of the AMPAR, and dominant-negative Ras inhibited synaptic potentiation in response to repetitive stimulation, which suggests a role for Ras in synaptic plasticity associated with long-term potentiation. In contrast, dominant-negative Rap enhanced tonic AMPAR activity, whereas wild-type Rap inhibited tonic AMPAR activity. Rap stimulated the phosphorylation of the p38 mitogen-activated protein kinase (MAPK). Also, the ability of active Rap to depress synaptic activity was blocked if the slices were treated with a p38 MAPK inhibitor. Dominant-negative Rap blocked the induction of long-term depression. Rap appeared to promote the removal of the same AMPAR subtypes that were removed from synapses during long-term depression, the short-tailed AMPAR subunits. Thus, Ras and Rap antagonize each other for regulation of AMPAR synaptic activity. J. J. Zhu, Y. Qin, M. Zhao, L. Van Aelst, R. Malinow, Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110 , 443-455 (2002). [Online Journal]