Integrin-type signaling has a distinct influence on NMDA-induced cytoskeletal disassembly.
Adhesion responses triggered by integrin-class matrix receptors have been implicated in the synaptic reorganization events necessary for certain types of neuronal plasticity. Hippocampal slice cultures were used to test whether the related structural transformations elicited by NMDA receptor stimulation are regulated by integrin-type signals. Infusing the slices with NMDA for a short period induced the expected disassembly of the cytoskeletal network, measured with antibodies that selectively recognize spectrin cleavage sites targeted by the protease calpain. Marked levels of the 150-kDa breakdown product (BDP) were produced, whereas concentrations of the parent spectrin were not changed. Interestingly, the calpain cleavage events were attenuated by 60% when integrin-type signaling was disrupted with the antagonist Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP). This effect was RGDS-dependent, was largely evident in synapse-dense dendritic areas, particularly in subfield CA1, and was abolished when the NMDA exposure period was >5 min. These findings suggest that only those cytoskeletal alterations associated with brief synaptic activity are regulated by intact contact zones. AMPA-type glutamate receptors also were tested because, like spectrin, they are targets for calpain. Brief NMDA treatment caused a 15% loss of AMPA receptor GluR1 carboxytermini and this modification was augmented to 32% in the presence of GRGDSP. Thus, although blockage of matrix recognition signals decreased spectrin's susceptibility to disassembly, it increased the susceptibility of AMPA receptors to proteolysis. These data indicate that integrin-type signaling complexes are appropriately positioned to govern cytoskeletal reconfiguration while stabilizing the structural nature of AMPA receptors.
Bahr
B A
BA
Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT 06269-2092, USA. Bahr@uconn.edu
D000818:Animals; D000831:Animals, Newborn; D002154:Calpain / Q000187:drug effects / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D016023:Integrins / Q000187:drug effects* / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013049:Spectrin / Q000187:drug effects / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D016023:Integrins; D013049:Spectrin; D016202:N-Methylaspartate; D002154:Calpain