期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 30, 页码 11376-11380出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0600768103
关键词
hepatic encephalopathy; mesolimbic dopamine; Parkinson's disease; proton gating; cirrhosis
资金
- NIDA NIH HHS [R01 DA009411, DA09411] Funding Source: Medline
- NINDS NIH HHS [NS21229, NS048505, R37 NS021229, R01 NS048505, R01 NS021229] Funding Source: Medline
Acid-sensitive ion channels (ASICs) are proton-gated and belong to the family of degenerin channels. In the mammalian nervous system, ASICs are most well known in sensory neurons, where they are involved in nociception, occurring when injury or inflammation causes acidification. ASICs also are widely expressed in the CNS, and some synaptic roles have been revealed. Because neuronal activity can produce pH changes, ASICs may respond to local acidic transients and alter the excitability of neuronal circuits more widely than is presently appreciated. Furthermore, ASICs have been found to underlie calcium transients that contribute to neuronal death. Degeneration of midbrain dopamine neurons Is characteristic of advanced idiopathic Parkinson's disease. Therefore, we tested for functional ASICs in midbrain dopamine neurons of the ventral tegmental area and substantial nigra compacta. Patch-clamp electrophysiology applied to murine midbrain slices revealed abundant acid-sensitive channels. The ASICs were gated and desensitized by extracellular application of millimolar concentrations of NH4CI. Although the NH4CI solution contains micromolar concentrations of NH3 at pH 7.4, our evidence indicates that NH4 gates the ASICs. The proton-gated and the ammonium-gated currents were inhibited by tarantula venom (psalmotoxin), which is specific for the ASIC1a subtype. The results show that acid-sensitive channels are expressed in midbrain dopamine neurons and suggest that ammonium sensitivity is a widely distributed ASIC characteristic in the CNS, including the hippocampus. The ammonium sensitivity suggests a role for ASIC1s in hepatic encephalopathy, cirrhosis, and other neuronal disorders that are associated with hyperammonemia.
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