Heteromultimers of DEG/ENaC subunits form H-gated channels in mouse sensory neurons

Department of Internal Medicine and Psychiatry, and Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2002; 99(4):2338-43. DOI: 10.1073/pnas.032678399
Source: PubMed


Acidic extracellular solution activates transient H(+)-gated currents in dorsal root ganglion (DRG) neurons. The biophysical properties of three degenerin/epithelial sodium (DEG/ENaC) channel subunits (BNC1, ASIC, and DRASIC), and their expression in DRG, suggest that they might underlie these H(+)-gated currents and function as sensory transducers. However, it is uncertain which of these DEG/ENaC subunits generate the currents, and whether they function as homomultimers or heteromultimers. We found that the biophysical properties of transient H(+)-gated currents from medium to large mouse DRG neurons differed from BNC1, ASIC, or DRASIC expressed individually, but were reproduced by coexpression of the subunits together. To test the contribution of each subunit, we studied DRG from three strains of mice, each bearing a targeted disruption of BNC1, ASIC, or DRASIC. Deletion of any one subunit did not abolish H(+)-gated currents, but altered currents in a manner consistent with heteromultimerization of the two remaining subunits. These data indicate that combinations of two or more DEG/ENaC subunits coassemble as heteromultimers to generate transient H(+)-gated currents in mouse DRG neurons.

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    • "They have also been detected in non-neural tissues, such as cancer cells [7], intestinal epithelial cells [8] and smooth muscle cells [9] [10]. Subunits encoded by the four ASIC genes may form homo-and heterotrimers with distinct acid-activated currents [11] [12]. ASICs are generally less sensitive to amiloride inhibition than ENaC [13]. "
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    ABSTRACT: ASIC and ENaC are co-expressed in various cell types, and there is evidence for a close association between them. Here, we used atomic force microscopy (AFM) to determine whether ASIC1a and ENaC subunits are able to form cross-clade hybrid ion channels. ASIC1a and ENaC could be co-isolated from detergent extracts of tsA 201 cells co-expressing the two subunits. Isolated proteins were incubated with antibodies against ENaC and Fab fragments against ASIC1a. AFM imaging revealed proteins that were decorated by both an antibody and a Fab fragment with an angle of ∼120° between them, indicating the formation of ASIC1a/ENaC heterotrimers. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 05/2015; 464(1). DOI:10.1016/j.bbrc.2015.05.091 · 2.30 Impact Factor
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    • "In contrast to Asic3−/− mice, which is presenting a phenotype of decreased sympathetic function, Asic2−/− mice had exaggerated sympathetic and depressed parasympathetic control of the circulation. Accumulating evidence has shown that ASIC2 assembles with ASIC3 to form functional heteromeric channels, especially in cardiac sensory neurons [21, 29, 48]. Besides, our previous study also suggests that ASIC3 of nodose ganglia plays a role in low-threshold baroreceptor in regulating blood volume homeostasis [36]. "
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    ABSTRACT: Integration of sympathetic and parasympathetic outflow is essential in maintaining normal cardiac autonomic function. Recent studies demonstrate that acid-sensing ion channel 3 (ASIC3) is a sensitive acid sensor for cardiac ischemia and prolonged mild acidification can open ASIC3 and evoke a sustained inward current that fires action potentials in cardiac sensory neurons. However, the physiological role of ASIC3 in cardiac autonomic regulation is not known. In this study, we elucidate the role of ASIC3 in cardiac autonomic function using Asic3 (-/-) mice. Asic3 (-/-) mice showed normal baseline heart rate and lower blood pressure as compared with their wild-type littermates. Heart rate variability analyses revealed imbalanced autonomic regulation, with decreased sympathetic function. Furthermore, Asic3 (-/-) mice demonstrated a blunted response to isoproterenol-induced cardiac tachycardia and prolonged duration to recover to baseline heart rate. Moreover, quantitative RT-PCR analysis of gene expression in sensory ganglia and heart revealed that no gene compensation for muscarinic acetylcholines receptors and beta-adrenalin receptors were found in Asic3 (-/-) mice. In summary, we unraveled an important role of ASIC3 in regulating cardiac autonomic function, whereby loss of ASIC3 alters the normal physiological response to ischemic stimuli, which reveals new implications for therapy in autonomic nervous system-related cardiovascular diseases.
    04/2014; 2014:709159. DOI:10.1155/2014/709159
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    • "Electrophysiological studies of hippocampal, cortical, and spinal cord neurons identified acid-evoked currents that are the result of a combination of ASIC1a homomers, ASIC1a/2a heteromers, and ASIC1a/2b heteromers [5], [7], [36], [37]. Compared to ASIC1a homomers, ASIC1a/2a heteromers are slightly less pH sensitive and have faster kinetics of desensitization [3], [4]. When ASIC2b heteromultimerizes with ASIC1a in CNS neurons, ASIC2b imparts altered pharmacology and slight shifts in ion selectivity [37]. "
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    ABSTRACT: Acid-sensing ion channels (ASICs) are Na+ channels activated by changes in pH within the peripheral and central nervous systems. Several different isoforms of ASICs combine to form trimeric channels, and their properties are determined by their subunit composition. ASIC2 subunits are widely expressed throughout the brain, where they heteromultimerize with their partnering subunit, ASIC1a. However, ASIC2 contributes little to the pH sensitivity of the channels, and so its function is not well understood. We found that ASIC2 increased cell surface levels of the channel when it is coexpressed with ASIC1a, and genetic deletion of ASIC2 reduced acid-evoked current amplitude in mouse hippocampal neurons. Additionally, ASIC2a interacted with the neuronal synaptic scaffolding protein PSD-95, and PSD-95 reduced cell surface expression and current amplitude in ASICs that contain ASIC2a. Overexpression of PSD-95 also reduced acid-evoked current amplitude in hippocampal neurons. This result was dependent upon ASIC2 since the effect of PSD-95 was abolished in ASIC2-/- neurons. These results lend support to an emerging role of ASIC2 in the targeting of ASICs to surface membranes, and allows for interaction with PSD-95 to regulate these processes.
    PLoS ONE 04/2014; 9(4):e93797. DOI:10.1371/journal.pone.0093797 · 3.23 Impact Factor
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