CALCIUM-PERMEABLE ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONIC-ACID RECEPTORS - A MOLECULAR DETERMINANT OF SELECTIVE VULNERABILITY IN AMYOTROPHIC-LATERAL-SCLEROSIS

The cause of the selective degeneration of motor neurons in amyotrophi c lateral sclerosis (ALS) remains unexplained, One potential pathogene tic mechanism is chronic toxicity due to disturbances of the glutamate rgic neurotransmitter system, mediated via alpha-amino-3-hydroxy-5-met hyl-4-isoxazole propionic acid (AA IPA)-sensitive glutamate receptors, Functional AMPA receptors consist of various combinations of four sub units (designated GluR1-4). The GluR2 subunit is functionally dominant and renders AMPA receptors impermeable to calcium, Most native AMPA r eceptors in the mammalian central nervous system (CNS) contain the Glu R2 subunit and are calcium impermeable. We have investigated the compo sition of AMPA receptors expressed on normal human spinal motor neuron s by in situ hybridization to determine their likely subunit stoichiom etry, Highly significant levels of mRNA were detected for the GluR1, G luR3, and GluR4 subunits. However, GluR2 subunit mRNA was not detectab le in this cell group, The absence of detectable GluR2 mRNA in normal human spinal motor neurons predicts that they express calcium-permeabl e AMPA receptors unlike most neuronal groups in the human CNS. Express ion of atypical calcium-permeable AMPA receptors by human motor neuron s provides a possible mechanism whereby disturbances of glutamate neur otransmission in ALS may selectively injure this cell group.