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

Department of Internal Medicine, University of Iowa, Iowa City, Iowa, United States
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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    • "By fitting the desensitization phase of the currents to a single exponential and recording the time constants of desensitization (τ), we found that ASIC-like currents from muscle afferents from both control and heart failure mice desensitize very fast (Fig. 5). Given our previous data, these fast kinetics indicate that the ASIC channels in muscle afferents from both groups of mice are heteromeric channels; only heteromeric channels that contain ASIC3 as one of the subunits possess such fast desensitization kinetics (τ < 0.2 s) for currents evoked by pH 6 (Benson et al. 2002; Hattori et al. 2009). At a couple of pH values tested, the desensitization kinetics were altered in heart failure mice. "
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    ABSTRACT: Heart failure is associated with diminished exercise capacity, which is driven, in part, by alterations in exercise-induced autonomic reflexes triggered by skeletal muscle sensory neurons (afferents). These overactive reflexes may also contribute to the chronic state of sympathetic excitation, which is a major contributor to the morbidity and mortality of heart failure. Acid-sensing ion channels (ASICs) are highly expressed in muscle afferents where they sense metabolic changes associated with ischemia and exercise, and contribute to the metabolic component of these reflexes. Therefore, we tested if ASICs within muscle afferents are altered in heart failure. We used whole-cell patch-clamp to study the electrophysiological properties of acid-evoked currents in isolated, labeled muscle afferent neurons from control and heart failure (induced by myocardial infarction) mice. We found that the percentage of muscle afferents that displayed ASIC-like currents, the current amplitudes, and the pH dose-response relationships were not altered in mice with heart failure. On the other hand, the biophysical properties of ASIC-like currents were significantly different in a subpopulation of cells (40%) from heart failure mice. This population displayed diminished pH sensitivity, altered desensitization kinetics, and very fast recovery from desensitization. These unique properties define these channels within this subpopulation of muscle afferents as being heteromeric channels composed of ASIC2a and -3 subunits. Heart failure induced a shift in the subunit composition of ASICs within muscle afferents, which significantly altered their pH sensing characteristics. These results might, in part, contribute to the changes in exercise-mediated reflexes that are associated with heart failure. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Aug 2015 · The Journal of Physiology
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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.
    Full-text · Article · May 2015 · Biochemical and Biophysical Research Communications
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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.
    Full-text · Article · Apr 2014
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