Lotta von Ossowski

University of Helsinki
Supervisor: Kari Keinänen
Funding: other
Date: 03/01/2002

Stargazin family proteins and their interaction with AMPA-selective glutamate receptors

Stargazin, a membrane protein highly expressed in the cerebellum, is reported to directly interact with AMPA-selective glutamate receptors and be critically involved in their cellular transport by an as yet uncharacterized mechanism1. Stargazin was first identified as a homologue of the gamma-subunit of voltage-gated calcium channels, defective in the epileptic mouse mutant stargazer2, which lack functional synaptic AMPA receptors in cerebellar granule cells. Subsequently, several further g-subunit homologues have been cloned: gamma3-gamma8. Stargazin (“gamma2”) and the closely related gamma3, gamma4, and gamma8 polypeptides share a long C-terminal hydrophilic segment which ends in a typical PDZ Type I binding motif, and are here collectively referred to as stargazins. The interaction between stargazin and PDZ-proteins like PSD-95 play an important role in guiding the AMPA receptors to the synapse1. The N-terminal part of stargazins contains a (predicted) four-transmembrane-span segment similar to the gamma subunit of voltage-gated calcium channel (gamma1), and to the related gamma5, gamma6, and gamma7 polypeptides, and more distantly to claudins, a membrane protein family involved in hetero- and homomeric cell-cell contacts.

Very little is known on the structure, function and properties of stargazins, which in addition to being important regulators of glutamate receptor function, are likely to have other important functions in the nervous system. This research project focuses on molecular characterization of stargazin proteins and their interactions with the AMPA receptor and other neuronal proteins. The goals of this study are: 1. Biochemical characterization of stargazin(s) and their interactions with AMPA receptors. 2. Determination of the three-dimensional structure of stargazin and/or its structural domains.

References:
1. Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408: 936-943.
2. Letts VA, Felix R, Biddlecome GH, Arikkath J, Mahaffey CL, Valenzuela A, Bartlett FS 2nd, Mori Y, Campbell KP & Frankel WN (1998) The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit. Nat Genet.19:340-347.