The Lipid Peroxidation Product 4-Hydroxynonenal Potently and Selectively Inhibits Synaptic Plasma Membrane Ecto-ATPase Activity,A Putative Regulator of Synaptic ATP and Adenosine |
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Authors: | Foley Timothy D. |
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Affiliation: | (1) Section on Neurochemistry, LCS, DICBR, National Institute on Alcohol Abuse and Alcoholism, NIH, 12420 Parklawn Drive, Room 158, Rockville, MD, 20852. Phone:;(2) Section on Biochemistry, Department of Chemistry, University of Scranton, Loyola Hall, Scranton, PA, 18510 |
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Abstract: | Synaptic plasma membrane (SPM)-bound, extracellular-facing (ecto) ATPases are Mg2+- or Ca2+-activated enzymes that regulate the synaptic levels of the excitatory neurotransmitter ATP and provide ADP for the further ecto-nucleotidase-mediated production of the inhibitory neuromodulator adenosine. The present results show that low concentrations (IC50 = 4 M) of the lipid peroxidation product 4-hydroxynonenal (HNE) inhibited up to about 80% of the ecto-ATPase activity of SPM purified from rat brain cerebral cortex. In contrast, low concentrations of HNE did not inhibit the activity of the intracellular-facing Na+, K+, Mg2+-ATPase. In addition, the inhibition of SPM ecto-ATPase activity by HNE was largely irreversible and pH-dependent. Furthermore, structure-activity studies demonstrate that inhibition was dependent on the presence of the reactive functional groups of HNE. These findings suggest that HNE selectively inhibits SPM ecto-ATPase activity by a mechanism that may involve the covalent modification of functionally-critical nucleophilic amino acids. It is proposed that inhibition of SPM ecto-ATPase activity could contribute to the mechanisms by which lipid peroxidation and HNE formation promote excitotoxicity. |
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Keywords: | 4-Hydroxynonenal ecto-ATPase synaptic plasma membranes excitotoxicity |
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