NEUROBIOLOGY Stargazin Transports AMPA Receptors

Abstract:

The murine stargazer phenotype is manifested by ataxia and epileptic seizures and is caused by mutations in the stargazin protein. Chen et al. describe the role of stargazin in the proper localization of AMPA (-amino-3-hydroxyl-5-methyl-4-isoxazole propionate) receptors but not NMDA (N-methyl-D-aspartate) receptors. On the basis of its sequence, stargazin was thought possibly to function as a -like subunit of neural Ca²⁺ channel function in stargazin homozygous mutant granule cells. Such cells exhibited no spontaneous AMPA receptor (AMPAR)-mediated currents or any response to glutamate though AMPAR, whereas NMDAR currents were unchanged. The amounts of AMPAR subunits GluR2 and GluR4 at synapses of stargazer mutant cells were greatly reduced. Stargazin associated with GluR4 and the PDZ protein PSD-95 (postsynaptic density-95), and association with PSD-95 required the stargazin COOH-terminus. However, deletion of the COOH-terminal region (stargazinC) had no effect on the association of stargazin with AMPARs. Overexpression of stargazin in mutant granule cells restored spontaneous and gluatamate-dependent activation of AMPAR; however, overexpression of stargazinC greatly decreased synaptic localization of AMPARs. Thus the truncated stargazin protein appears to deliver AMPAR to the plasma membrane, but interaction with PSD-95 or other proteins though the COOH-terminus is required for delivery of AMPARs to synapses.

Chen, L., Chetkovich, D.M., Petralia, R.S., Sweeney, N.T., Kawasaki, Y., Wenthold, R.J., Bredt, D.S., and Nicoll, R.A. (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408: 936-943. [Online Journal]