The GluR2 Hypothesis: Ca++-permeable AMPA Receptors in Delayed Neurodegeneration

  1. M.V.L. Bennett1,
  2. D.E. Pellegrini-Giampietro2,
  3. J.A. Gorter1,4,
  4. E. Aronica1,
  5. J.A. Connor3,5, and
  6. R.S. Zukin1
  1. 1Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461; 2Dipartimento di Farmacologia Preclinica e Clinica “Mario Aiazzi Mancini,” Universita di Firenze, 50134 Firenze, Italy; 3Roche Institute of Molecular Biology, Nutley, New Jersey 07110; 4University of Amsterdam, Dept. Experimentele Dierkunde, 1098 SM Amsterdam, The Netherlands; 5The Lovelace Institute, Albuquerque, New Mexico 87108

This extract was created in the absence of an abstract.

Excerpt

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. Diseases such as Alzheimer's and Huntington's may also involve overstimulation of glutamate receptors. A major cytotoxic mechanism is increased Ca++ influx through NMDA receptors and voltage-activated Ca++ channels, and under conditions of metabolic stress, reduced Ca++ extrusion and sequestration. Until recently, non-NMDA receptors were thought to be Ca++-impermeable, but it is now well established that AMPA receptors lacking the GluR2 subunit are Ca++-permeable and provide an additional potential source of Ca++ overload (for references, see below). High levels of cytosolic Ca++ are known to induce cell degeneration by activation of proteases and endonucleases (for reviews, see Rothman and Olney 1986; Choi 1988, 1992; Sheardown et al. 1990). In cultured neurons, sufficiently high Ca++ levels induce necrosis, but lower levels can also induce apoptosis (Takei and...

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