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The Journal of Neuroscience, May 19, 2004, 24(20):4758-4766; doi:10.1523/JNEUROSCI.0594-04.2004

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Cellular/Molecular
Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Nashaat Z. Gerges,¹ Irwin C. Tran,¹ Donald S. Backos,¹ Jennifer M. Harrell,¹ Michael Chinkers,² William B. Pratt,¹ and José A. Esteban¹

¹Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, and ²Department of Pharmacology, University of South Alabama, Mobile, Alabama 36688

The delivery of neurotransmitter receptors into synapses is essential for synaptic function and plasticity. In particular, AMPA-type glutamate receptors (AMPA receptors) reach excitatory synapses according to two distinct routes: a regulated pathway, which operates transiently during synaptic plasticity, and a constitutive pathway, which maintains synaptic function under conditions of basal transmission. However, the specific mechanisms that distinguish these two trafficking pathways are essentially unknown. Here, we evaluate the role of the molecular chaperone hsp90 (heat shock protein 90) in excitatory synaptic transmission in the hippocampus. On one hand, we found that hsp90 is necessary for the efficient neurotransmitter release at the presynaptic terminal. In addition, we identified hsp90 as a critical component of the cellular machinery that delivers AMPA receptors into the postsynaptic membrane. Using the hsp90-specific inhibitors radicicol and geldanamycin, we show that hsp90 is required for the constitutive trafficking of AMPA receptors into synapses during their continuous cycling between synaptic and nonsynaptic sites. In contrast, hsp90 function is not required for either the surface delivery of AMPA receptors into the nonsynaptic plasma membrane or for the acute, regulated delivery of AMPA receptors into synapses during plasticity induction (long-term potentiation). The synaptic cycling of AMPA receptors was also blocked by an hsp90-binding tetratricopeptide repeat (TPR) domain, suggesting that the role of hsp90 in AMPA receptor trafficking is mediated by a TPR domain-containing protein. These results demonstrate new roles for hsp90 in synaptic function by controlling neurotransmitter release and, independently, by mediating the continuous cycling of synaptic AMPA receptors.

Key words: AMPA receptor trafficking; hippocampus; LTP; radicicol; TPR domain; CA1

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Received Dec 1, 2003; revised April 5, 2004; accepted April 5, 2004.

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