Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage

Abstract

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 substantia 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 NH 4Cl. Although the NH4Cl solution contains micromolar concentrations of NH3 at pH 7.4, our evidence indicates that NH 4 ؉ 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 acidsensitive 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.hepatic encephalopathy ͉ mesolimbic dopamine ͉ Parkinson's disease ͉ proton gating ͉ cirrhosis P roton-gated channels or acid-sensitive ion channels (ASICs) are present in sensory neurons, where they have roles in nociception, taste, and possibly other modalities (1-5). Recently, six ASIC subunits were cloned (6, 7) and identified as belonging to a broad family of degenerin (Deg) channels. ASIC1a (also known as BNaC2) and ASIC1b (ASIC1␤) are the splice variants of the ASIC1 gene (6,8,9). ASIC2a (BNaC1, MDEG) and ASIC2b (MDEG2) are the spliced forms of the ASIC2 gene (10). Other subunits are ASIC3 (DRASIC) (7, 11) and ASIC4 (SPA-SIC) (12, 13). The ASIC subunits form a variety of heteromeric channels in heterologous expression systems, and subunits other than ASIC2b and ASIC4 also form functional homomeric channels in expression systems (14).Although there has been much progress, there is still uncertainty about the pharmacology, the endogenous subunit composition, and the functional significance of different CNS ASIC subtypes (4,5,15,16). ASIC1 is the subunit most abundantly expressed in the mammalian brain and has been shown to be involved in synaptic plasticity (17). ASICs in the CNS also have been implicated in Ca 2ϩ toxicity arising from ischemia, and inhibition or knockout of ASIC1 protected the ...

Parkin-mediated Monoubiquitination of the PDZ Protein PICK1 Regulates the Activity of Acid-sensing Ion Channels

“…Thus, the current work showing that endogenous parkin masks PICK1-dependent ASIC potentiation in hippocampal neurons suggests that it might also normally protect neurons from channel overactivity leading to excitotoxicity. Because ASICs have recently been implicated in midbrain dopamine neuron injury (Pidoplichko and Dani, 2006), the unmasking of ASIC current potentiation in parkin knockout neurons may reflect an increased vulnerability of these neurons to injury in patients with PD-associated parkin mutations. …”

Evidence for ammonium conductance in a mouse thick ascending limb cell line

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