Glutamate Regulates Dystrophin-71 levels in Glia Cells Roque Galaz-Vega, 1 Luisa C. R. Herna´ndez-Kelly, 1 J. Alfredo Me´ndez, 1 Bulmaro Cisneros, 1 and Arturo Ortega 1,2 (Accepted December 15, 2004) Glial glutamate receptors are likely to be involved in neuronal differentiation, migration, and plasticity. Dystrophin, the protein defective in Duchenne muscular dystrophy (DMD) is widely expressed in the Central Nervous System. Activation of internal promoters of the DMD gene leads to the production of several proteins, the Dystrophin-71 (Dp-71) being the most abundant in the encephalon. This protein is known to stabilize neurotransmitter receptors in clusters and its absence has been correlated with cognitive deficits in a mouse model. Using cultured chick Bergmann glia cells and mouse cerebellar fusiform astrocytes, we demonstrate here that glutamate receptor activation results in a time and dose dependent decrease of Dp-71 levels. This effect is mediated through ~ aamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The present results suggest an involvement of Dp-71 in glutamate receptor signaling and possibly clustering and further support the notion of an active role of glia in the physiology of glutamatergic transmission. KEY WORDS: Dystrophin; glutamate receptors; Bergmann glia; astrocytes; signal transduction. INTRODUCTION Glutamate is the main excitatory neurotransmitter in the vertebrate brain. To elicit its functions, glutamate activates two types of receptors: ligand-gated ion channels (iGluRs) and metabotropic receptors (mGluRs) coupled to G proteins. The iGluRs have been subdivided in N-methyl-D-aspartate (NMDA), AMPA and kainate (KA) receptors (1). Metabotropic receptors are preferentially activated by quisqualate (Quis), ibonate (IBO) and (1S,3R)-1-aminocyclopena- tane-1,3-dicarboxylate (trans-ACPD) (2). Glial cells express both types of glutamate receptors, suggesting a role for these cells in the neuronal transactions of the synapses surrounded by them. In the cerebellum, Bergmann glia cells extend ra- dial processes through the molecular layer in contact with excitatory and inhibitory synapses (3). Activation of Bergmann glia receptors is linked to diverse signal- ing pathways that regulate gene expression. Further- more, when the composition of their AMPA receptors is altered, a dramatic change of cell morphology oc- curs, not only in the glial cells, but also in the Purkinje neurons (4). Therefore, a continuous signaling between glial and neuronal cells takes place in vivo. The subcellular distribution of glutamate recep- tors in nerve cells implies an underlying mechanism for discrete localization patterns, in which the bind- ing to proteins that contain PDZ (PSD-95/Discs large/ZO-1) domains plays a major role (5). The dystrophin glycoprotein complex (DGC) is a mem- brane-spanning group of proteins that interacts with PDZ-containing proteins forming multiprotein com- plexes apparently involved in signal transduction. Dystrophin, the first protein described as a product of the Duchenne muscular dystrophy (DMD) gene, is a 427 kDa polypeptide. Activation of internal promoters leads to the expression of seven protein products designated according to their 1 Departamento de Gene´tica y Biologı´a Molecular Cinvestav-IPN Apartado Me´xico. 2 Address reprint requests to: Arturo Ortega, Ph.D. Fax: 01-5255- 747-3800, Extn 5317; E-mail: arortega@cinvestav.mx Neurochemical Research, Vol. 30, No. 2, February 2005 (Ó 2005), pp. 237–243 DOI: 10.1007/s11064-004-2446-6 237 0364-3190/05/0200–0237/0 Ó 2005 Springer Science+Business Media, Inc.