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  • br Experimental methods br Acknowledgments We


    Experimental methods
    Acknowledgments We thank all members of the Hermanson lab, especially Ana Teixeira, Shirin Ilkhanizadeh and Karolina Wallenborg, for assistance and discussions, Peter Löw for anti-synaptotagmin antibody, and Lars Björklund, Ole Isacson, Christer Höög, Claes Wahlestedt and Jamie Timmons for support. Supported by grants from the Swedish Research Council (VR), Knut and Alice Wallenberg Foundation (CLICK), the Swedish Foundation for Strategic Research (SSF (CEDB)), the Jeansson Foundation, the Åke Wiberg Foundation, (O.H. and P.U.), Fredrik and Ingrid Thuring Foundation (P.U.), the Swedish Childhood Cancer Foundation(BCF), the Swedish Cancer Society (CF), the Åhlén Foundation, the Wenner-Gren Foundation, the Swedish Medical Society, and Karolinska Institutet (O.H.).
    Glutamate receptors mediate excitatory neurotransmission and play a crucial role in synaptogenesis and formation of neuronal circuitry, as well as in synaptic plasticity including long-term 5-Carboxymethylester-UTP potentiation and long-term depression. Excessive activation of glutamate receptors is thought to contribute to neurodegeneration following a wide range of neurological insults including ischemia, trauma, hypoglycemia and epileptic seizures. Chronic neurodegenerative disorders such as Alzheimer's disease, Huntington's chorea, AIDS encephalopathy, and amyotrophic lateral sclerosis might also involve glutamate-induced neuronal cell death, . Considerable interest has focused on the molecular mechanisms underlying glutamate-induced neurodegeneration. Glutamate induces cell death by increasing the [Ca] in neurons, thereby leading to generation of free radicals and activation of proteases, phospholipases and endonucleases, , as well as transcriptional activation of specific `cell death' programs. Glutamate can produce a rise in cytosolic Ca by a number of mechanisms including: (1) activation of Ca-permeable NMDA receptors; (2) opening of voltage-dependent Ca 5-Carboxymethylester-UTP following membrane depolarization induced by activation of AMPA receptors; and (3) activation of metabotropic glutamate receptors linked to phosphoinositide hydrolysis, which releases Ca from intracellular stores. Until recently, AMPA receptors were thought to be Ca-impermeable. It is now well established that AMPA receptors lacking the GluR2 subunit are permeable to a number of divalent cations including Ca. The GluR2 hypothesis predicts that specific neurological insults lead to a decrease in GluR2 expression and formation of Ca-permeable AMPA receptors, and thereby, enhanced toxicity of endogenous glutamate. This article reviews the recent experimental evidence that Ca- permeable AMPA receptors contribute to the delayed and cell-specific neurodegeneration associated with transient forebrain ischemia and kainate-induced status epilepticus.
    AMPA-type glutamate receptors mediate fast excitatory synaptic transmission in the vertebrate central nervous system. AMPA receptors are ligand-gated channels that are thought to be pentamers assembled from GluR1, 2, 3 and 4 (or GluR-A, -B, -C and -D) subunits6, 7, 8 around a central aqueous pore. The predicted secondary structure of Glu-receptor subunits (Fig. 1) includes the following features: (1) a large extracellular N-terminus domain; (2) three transmembrane-spanning domains (TM1, TM3 and TM4); (3) a fourth hydrophobic segment (M2) that forms a channel-lining re-entrant hairpin loop similar to the pore-forming region of K+ channels[9]; (4) a binding domain for agonists formed from the S1 and S2 extracellular regions[10]; and (5) an intracellular C-terminus domain. Glu-receptor subunits appear to be expressed by all neurons in the brain, although each cell can differ in the number and type of subunits expressed. Individual neurons form predominantly heteromeric AMPA receptors made up of at least two different subunits, but they can also form homomers13, 14. The first demonstrations that GluR2 determines Ca2+ permeability of AMPA receptors came from electrophysiological studies of recombinant AMPA channels expressed in Xenopus laevis oocytes[15] and mammalian cells[16]. AMPA receptors assembled from GluR1, GluR3 or GluR4 alone or in combination are permeable to Ca2+ and have doubly rectifying current–voltage relationships. GluR2, expressed with other GluR subunits, forms channels that are Ca2+-impermeable and electrically linear or outwardly rectifying (Fig. 2). The dominance of the GluR2 subunit in determining permeability to Ca2+ and other divalent ions is attributed to the presence of a positively charged arginine (R) in place of a glutamine (Q) residue within the M2 domain11, 20. Rectification of receptors lacking GluR2 arises from fast voltage-dependent channel block by intracellular polyamines21, 22. Some positively charged polyamine spider toxins like argiotoxin[23] and Joro spider toxin[24] block Ca2+-permeable AMPA receptors selectively (presumably because they are repelled by the positively charged arginine residue in the GluR2 subunit) and therefore serve as pharmacological probes to detect the presence or absence of GluR2 in recombinant (as well as in native) receptor assemblies.