The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function

Page, Amanda J.; Brierley, Stuart M.; Martin, Christopher M.; Martı́nez-Salgado, Carlos; Wemmie, John A.; Brennan, Timothy J.; Symonds, Erin L.; Omari, Taher; Lewin, Gary R.; Welsh, Michael J.; Blackshaw, L. Ashley

doi:10.1053/j.gastro.2004.08.061

Cited by 135 publications

(119 citation statements)

References 31 publications

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“…Finally, although less likely, it is also possible that the channels containing mutant ASIC3 subunits, tested for the absence of response to protons, remain sensitive to other unidentified agonists that play a role in nociception. The expression of ASIC2 has been reported recently to protect against light-induced neurodegeneration in the retina (Ettaiche et al, 2004), and the knock-out of ASIC1 leads to hypersensitivity of visceral mechanoreceptors (Page et al, 2004). The hypersensitivity of transgenic animals expressing dominant-negative ASIC3 subunits to mechanical and inflammatory stimuli points also to a regulatory role for ASICs in sensory pathways.…”

Section: Asic Transgenic Mice Show Increased Sensitivity To Chemical/mentioning

confidence: 99%

Transgenic Expression of a Dominant-Negative ASIC3 Subunit Leads to Increased Sensitivity to Mechanical and Inflammatory Stimuli

Mogil

Breese²,

Witty³

et al. 2005

J. Neurosci.

113

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Molecular and behavioral evidence suggests that acid-sensing ion channels (ASICs) contribute to pain processing, but an understanding of their precise role remains elusive. Existing ASIC knock-out mouse experiments are complicated by the heteromultimerization of ASIC subunits. Therefore, we have generated transgenic mice that express a dominant-negative form of the ASIC3 subunit that inactivates all native neuronal ASIC-like currents by oligomerization. Using whole-cell patch-clamp recordings, we examined the response properties of acutely isolated dorsal root ganglion neurons to protons (pH 5.0). We found that whereas 33% of the proton-responsive neurons from wild-type mice exhibited an ASIC-like transient response, none of the neurons from the transgenic mice exhibited a transient inward current. Capsaicin-evoked responses mediated by the TRPV1 receptor were unaltered in transgenic mice. Adult male wild-type and transgenic mice were subjected to a battery of behavioral nociceptive assays, including tests of thermal, mechanical, chemical/inflammatory, and muscle pain. The two genotypes were equally sensitive to thermal pain and to thermal hypersensitivity after inflammation. Compared with wild types, however, transgenic mice were more sensitive to a number of modalities, including mechanical pain (von Frey test, tail-clip test), chemical/inflammatory pain (formalin test, 0.6% acetic acid writhing test), mechanical hypersensitivity after zymosan inflammation, and mechanical hypersensitivity after intramuscular injection of hypotonic saline. These data reinforce the hypothesis that ASICs are involved in both mechanical and inflammatory pain, although the increased sensitivity of transgenic mice renders it unlikely that they are direct transducers of nociceptive stimuli.

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Section: Asic Transgenic Mice Show Increased Sensitivity To Chemical/mentioning

confidence: 99%

Transgenic Expression of a Dominant-Negative ASIC3 Subunit Leads to Increased Sensitivity to Mechanical and Inflammatory Stimuli

Mogil

Breese²,

Witty³

et al. 2005

J. Neurosci.

113

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“…However, different mechanisms seem to underlie mechanosensory function in various tissues. In the gut and skin, for example, the de- (612).…”

Section: A Neuroanatomy and Neurophysiology Of Cutaneous Nervesmentioning

confidence: 99%

Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Roosterman¹,

Goerge

Schneider

et al. 2006

Physiological Reviews

548

521

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This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.

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“…Thus deletion of the ASIC2 and ASIC3 genes, but not the ASIC1 gene, leads to clear deficits in the mechanosensitivity of cutaneous mechanoreceptors and nociceptors (Price et al, 2000(Price et al, , 2001Page et al, 2004;Moshourab et al, 2013). However, it appears very unlikely that ASIC subunits are in fact necessary for the formation of a mechanosensitive current in DRG neurons as these appear unaltered following ASIC gene deletion (Drew et al, 2004;).…”

Section: Recordings From Nociceptors Innervating Uv-b Sensitized Skinmentioning

confidence: 99%

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

Lewin

Lechner

Smith

2014

Handbook of Experimental Pharmacology

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Nerve growth factor (NGF) is central to the development and functional regulation of sensory neurons that signal the first events that lead to pain. These sensory neurons, called nociceptors, require NGF in the early embryo to survive and also for their functional maturation. The long road from the discovery of NGF and its roles during development to the realization that NGF plays a major role in the pathophysiology of inflammatory pain will be reviewed. In particular, we will discuss the various signaling events initiated by NGF that lead to long lasting thermal and mechanical hyperalgesia in animals and in man. It has been realized relatively recently that humanized, function blocking antibodies directed against NGF show remarkably analgesic potency in human clinical trials for painful conditions as varied as osteoarthritis, lower back pain and interstitial cystitis. Thus, anti-NGF medication has the potential to make a major impact on day-to-day pain treatment in the near future. It is therefore all the more important to understand the precise pathways and mechanisms that are controlled by NGF to initiate and sustain mechanical and thermal hyperalgesia. Recent work suggests that NGF-dependent regulation of the mechanosensory properties of sensory neurons that signal mechanical pain may open new mechanistic avenues to refine and exploit relevant molecular targets for novel analgesics.

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The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function

Cited by 135 publications

References 31 publications

Transgenic Expression of a Dominant-Negative ASIC3 Subunit Leads to Increased Sensitivity to Mechanical and Inflammatory Stimuli

Transgenic Expression of a Dominant-Negative ASIC3 Subunit Leads to Increased Sensitivity to Mechanical and Inflammatory Stimuli

Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

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