Different contributions of ASIC channels 1a, 2, and 3 in gastrointestinal mechanosensory function

Nerve Gut Research Laboratory, Hanson Institute, Department of Gastroenterology, Hepatology and General Medicine, Royal Adelaide Hospital, Australia.
Gut (Impact Factor: 13.32). 11/2005; 54(10):1408-15. DOI: 10.1136/gut.2005.071084
Source: PubMed

ABSTRACT Members of the acid sensing ion channel (ASIC) family are strong candidates as mechanical transducers in sensory function. The authors have shown that ASIC1a has no role in skin but a clear influence in gastrointestinal mechanotransduction. Here they investigate further ASIC1a in gut mechanoreceptors, and compare its influence with ASIC2 and ASIC3.
Expression of ASIC1a, 2, and 3 mRNA was found in vagal (nodose) and dorsal root ganglia (DRG), and was lost in mice lacking the respective genes. Recordings of different classes of splanchnic colonic afferents and vagal gastro-oesophageal afferents revealed that disruption of ASIC1a increased the mechanical sensitivity of all afferents in both locations. Disruption of ASIC2 had varied effects: increased mechanosensitivity in gastro-oesophageal mucosal endings, decreases in gastro-oesophageal tension receptors, increases in colonic serosal endings, and no change in colonic mesenteric endings. In ASIC3-/- mice, all afferent classes had markedly reduced mechanosensitivity except gastro-oesophageal mucosal receptors. Observations of gastric emptying and faecal output confirmed that increases in mechanosensitivity translate to changes in digestive function in conscious animals.
These data show that ASIC3 makes a critical positive contribution to mechanosensitivity in three out of four classes of visceral afferents. The presence of ASIC1a appears to provide an inhibitory contribution to the ion channel complex, whereas the role of ASIC2 differs widely across subclasses of afferents. These findings contrast sharply with the effects of ASIC1, 2, and 3 in skin, suggesting that targeting these subunits with pharmacological agents may have different and more pronounced effects on mechanosensitivity in the viscera.

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Available from: Stuart M Brierley, Aug 23, 2015
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    • "In addition, there is increasing evidence that, besides TRP channels, ASIC channels play a role in various models of mechanical hypersensitivity to colorectal distension (Fig. 2). This implication is related to the property of molecular acid sensors to be affected by multiple sensory modalities including mechanical stimuli, which also applies to ASICs (Price et al., 2001; Page et al., 2005). Specifically, both ASIC3 and TRPV1 participate in the effect of zymosan to sensitize colonic mechanoreceptors of the mouse and to cause chronic behavioural hypersensitivity to colorectal distension in the absence of inflammation (Jones et al., 2007). "
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    ABSTRACT: Gastric acid is of paramount importance for digestion and protection from pathogens but, at the same time, is a threat to the integrity of the mucosa in the upper gastrointestinal tract and may give rise to pain if inflammation or ulceration ensues. Luminal acidity in the colon is determined by lactate production and microbial transformation of carbohydrates to short chain fatty acids as well as formation of ammonia. The pH in the oesophagus, stomach and intestine is surveyed by a network of acid sensors among which acid-sensing ion channels (ASICs) and acid-sensitive members of transient receptor potential ion channels take a special place. In the gut, ASICs (ASIC1, ASIC2, ASIC3) are primarily expressed by the peripheral axons of vagal and spinal afferent neurons and are responsible for distinct proton-gated currents in these neurons. ASICs survey moderate decreases in extracellular pH and through these properties contribute to a protective blood flow increase in the face of mucosal acid challenge. Importantly, experimental studies provide increasing evidence that ASICs contribute to gastric acid hypersensitivity and pain under conditions of gastritis and peptic ulceration but also participate in colonic hypersensitivity to mechanical stimuli (distension) under conditions of irritation that are not necessarily associated with overt inflammation. These functional implications and their upregulation by inflammatory and non-inflammatory pathologies make ASICs potential targets to manage visceral hypersensitivity and pain associated with functional gastrointestinal disorders.
    Neuropharmacology 01/2015; 315. DOI:10.1016/j.neuropharm.2014.12.009 · 4.82 Impact Factor
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    • "We observed reduced baseline mechanosensitivity in mesenteric but not serosal or muscular afferents, suggesting that Na V 1.9 may contribute to the regulation of excitability in this afferent subtype. Interestingly, mechanosensitivity is reduced in serosal , but not mesenteric, afferents in ASIC2 À/À mice [38] [48]. It remains to be seen whether differences in the expression of mechanotransducers or other known regulators of neuronal excitability (such as T-type calcium channels or HCN2) present in serosal vs mesenteric afferents contributes to the importance of Na V 1.9 in regulating afferent firing remains [12] [46]. "
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    ABSTRACT: Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal (GI) side effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 is required for normal mechanosensation, for direct excitation and for sensitisation of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE2 were substantially reduced in NaV1.9-/- mice. Deletion of NaV1.9 substantially attenuates excitation, and subsequent mechanical hypersensitivity, following application of inflammatory soup (bradykinin, ATP, histamine, PGE2 and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of NaV1.9 and there was a rightward shift in stimulus-response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however run-down of responses to repeat phasic distension were exacerbated in NaV1.9-/- afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in NaV1.9-/- mice. These results demonstrate that NaV1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity and is essential for activation by noxious inflammatory mediators including those from diseased human bowel. These observations indicate that NaV1.9 represents a high-value target for development of visceral analgesics.
    Pain 06/2014; 155(10). DOI:10.1016/j.pain.2014.06.015 · 5.84 Impact Factor
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    • "The acid-sensing ion channels (ASICs) are proton-gated trimeric channels (Gonzales et al., 2009; Jasti et al., 2007) that belong to the degenerin/epithelial sodium channel (DEG/ENaC) family (Kellenberger and Schild, 2002) and are implicated in ischemia (Gao et al., 2005; Sutherland et al., 2001; Xiong et al., 2004; Yagi et al., 2006), neurotransmission (Wemmie et al., 2002), epilepsy (Ziemann et al., 2008), mechanosensation (Lu et al., 2009; Page et al., 2005; Price et al., 2000, 2001), chemosensation (Ziemann et al., 2009), and pain perception (Chen et al., 2002; Deval et al., 2008; Duan et al., 2007; Mazzuca et al., 2007; Sluka et al., 2003; Xu and Duan, 2009). As their name indicates , ASICs are activated by extracellular acidosis (Krishtal, 2003; Waldmann et al., 1997; Wemmie et al., 2006). "
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    ABSTRACT: Acid-sensing ion channels (ASICs) have long been considered as extracellular proton (H(+))-gated cation channels, and peripheral ASIC3 channels seem to be a natural sensor of acidic pain. Here, we report the identification of a nonproton sensor on ASIC3. We show first that 2-guanidine-4-methylquinazoline (GMQ) causes persistent ASIC3 channel activation at the normal pH. Using GMQ as a probe and combining mutagenesis and covalent modification analysis, we then uncovered a ligand sensor lined by residues around E423 and E79 of the extracellular "palm" domain of the ASIC3 channel that is crucial for activation by nonproton activators. Furthermore, we show that GMQ activates sensory neurons and causes pain-related behaviors in an ASIC3-dependent manner, indicating the functional significance of ASIC activation by nonproton ligands. Thus, natural ligands beyond protons may activate ASICs under physiological and pathological conditions through the nonproton ligand sensor, serving for channel activation independent of abrupt and marked acidosis.
    Neuron 10/2010; 68(1):61-72. DOI:10.1016/j.neuron.2010.09.001 · 15.98 Impact Factor
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