Gastroenterology

Gastroenterology

Volume 127, Issue 6, December 2004, Pages 1739-1747
Gastroenterology

Basic-alimentary tract
The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function

https://doi.org/10.1053/j.gastro.2004.08.061Get rights and content

Background & Aims: Visceral mechanoreceptors are critical for perceived sensations and autonomic reflex control of gastrointestinal function. However, the molecular mechanisms underlying visceral mechanosensation remain poorly defined. Degenerin/epithelial Na+ channel (DEG/ENaC) family ion channels are candidate mechanosensory molecules, and we hypothesized that they influence visceral mechanosensation. We examined the influence of the DEG/ENaC channel ASIC1 on gastrointestinal mechanosensory function, on gastric emptying, and on fecal output. We also compared its role in gastrointestinal and somatic sensory function. Methods: To assess the role of ASIC1 we studied wild-type and ASIC1−/− mice. Reverse-transcription polymerase chain reaction (RT-PCR) and Western blot analysis determined expression of ASIC1 messenger RNA and protein in vagal and spinal sensory ganglia. Colonic, gastroesophageal, and cutaneous afferent fibers were characterized by functional subtype and their mechanical stimulus-response relationships were determined. Gastric emptying was determined by using a 13CO2 breath test. Behavioral tests assessed somatic mechanical and thermal sensitivity. Results: ASIC1 was expressed in sensory ganglia and was lost after disruption of the ASIC1 gene. Loss of ASIC1 increased mechanosensitivity in all colonic and gastroesophageal mechanoreceptor subtypes. In addition, ASIC1−/− mice showed almost double the gastric emptying time of wild-type mice. In contrast, loss of ASIC1 did not affect function in any of the 5 types of cutaneous mechanoreceptors, nor did it affect paw withdrawal responses or fecal output. Conclusions: ASIC1 influences visceral but not cutaneous mechanoreceptor function, suggesting that different mechanisms underlie mechanosensory function in gut and skin. The role of ASIC1 is highlighted by prolonging gastric emptying of a meal in ASIC1−/− animals.

Section snippets

Generation of ASIC1−/− mice

Mice with a disrupted ASIC1 gene were generated by homologous recombination in embryonic stem cells as we have described previously.13 In the targeted allele, a phosphoglycerate kinase (PGK)-neo cassette replaces the first exon of the ASIC1 gene and approximately 400 bp of upstream sequence. Heterozygote pairs of mice were mated to generate animals for the current investigation. Homozygous ASIC1+/+ or −/− littermates were selected blindly for experiments after genotyping and results were

ASIC1 is expressed in sensory neurons

By using RT-PCR analysis, we detected both ASIC1 splice variants (ASIC1a and ASIC1b) in the nodose ganglion (where cell bodies of vagal afferents are located) of +/+ mice (Figure 2A). It previously has been shown that ASIC1 also is expressed in DRG sensory neurons,25 which innervate the skin and colon. Consistent with those data, we found ASIC1a and 1b transcripts in DRG by RT-PCR (Figure 2A). In ASIC1−/− mice, ASIC1a transcripts were eliminated, although RT-PCR still could detect a signal for

Discussion

One of the key aims of current neurobiology is to identify a means of selectively modulating sensory input to the central nervous system. Thus, it is important to define mechanosensory mechanisms in specific populations of sensory neurons that supply different regions of the body. The gut relies on a wealth of mechanosensory input to maintain normal function. Thus, identifying the molecules that influence visceral mechanosensation may lead to an improved understanding of gastrointestinal

References (31)

  • W. Schwizer et al.

    Non-invasive measurement of gastric accommodation in humans

    Gut

    (2002)
  • M. Abo et al.

    Impairment of gastric and jejunal myoelectrical activity during rectal distension in dogs

    Dig Dis Sci

    (2000)
  • H. Abrahamsson et al.

    Vago-vagal gastro-gastric relaxation in the cat

    Acta Physiol Scand

    (1973)
  • I. Mano et al.

    DEG/ENaC channelsa touchy superfamily that watches its salt

    Bioessays

    (1999)
  • M. Driscoll et al.

    The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration

    Nature

    (1991)
  • Cited by (0)

    Supported by the National Health and Medical Research Council of Australia, Deutsche Forschungsgemeinshaft, and the Howard Hughes Medical Institute.

    1

    Carlos Martinez-Salgado is currently with the Unidad de Investigación, Hospital Universitario de Salamanca, Spain.

    2

    A.J.P., S.M.B., and C.M.M. contributed equally to this work.

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