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ACID-SENSING ION CHANNEL, SUBUNIT 2; ASIC2

ACID-SENSING ION CHANNEL, SUBUNIT 2; ASIC2

Alternative titles; symbolsCATION CHANNEL, AMILORIDE-SENSITIVE, NEURONAL, 1; ACCN1BRAIN SODIUM CHANNEL 1; BNAC1BNC1SODIUM CHANNEL, NONVOLTAGE-GATED, NEURONAL, 1M...

Alternative titles; symbols

  • CATION CHANNEL, AMILORIDE-SENSITIVE, NEURONAL, 1; ACCN1
  • BRAIN SODIUM CHANNEL 1; BNAC1
  • BNC1
  • SODIUM CHANNEL, NONVOLTAGE-GATED, NEURONAL, 1
  • MAMMALIAN DEGENERIN; MDEG

HGNC Approved Gene Symbol: ASIC2

Cytogenetic location: 17q11.2-q12 Genomic coordinates (GRCh38): 17:33,013,086-34,156,767 (from NCBI)

▼ Cloning and Expression
Price et al. (1996) cloned a novel cDNA encoding a nonvoltage-dependent sodium channel from human brain, which they termed BNC1. BNC1 has some sequence similarity to members of a family of amiloride-sensitive sodium channels that includes the mammalian epithelial Na+ channel (SCNN1A; 600228). However, among other dissimilarities, BNC1 channel activity did not increase when it was coexpressed with other cloned subunits of the family. Thus, Price et al. (1996) considered BNC1 to be the first cloned member of a novel subfamily of mammalian Na+ channels. Northern blot analysis detected 2.7- and 3.7-kb transcripts in brain and spinal cord only, suggesting that BNC1 may play a role in neurotransmission.

Mutations of the degenerins (deg-1, mec-4, mec-10) are the major causes of hereditary neurodegeneration in C. elegans. In the EST database, Waldmann et al. (1996) found and cloned a neuronal degenerin homolog from a human and rat brain library, which they designated MDEG. The MDEG protein contains 512 amino acids. Northern blot analysis revealed that MDEG mRNA was abundant in brain, specifically in neurons.

Garcia-Anoveros et al. (1997) isolated cDNAs encoding ACCN1 and ACCN2 (602866), which they designated BNaC1 and BNaC2, respectively. The predicted BNaC1 and BNaC2 proteins are 68% identical. Northern blot analysis and in situ hybridization of mouse brain showed that the 2 genes were coexpressed in most, if not all, brain neurons, and that they were expressed early in embryogenesis and throughout life.

Using quantitative real-time PCR, Jahr et al. (2005) detected ASIC1 (ACCN2), ASIC2, and ASIC3 (611741) expression in human skeletal biopsy specimens. These ASICs were also expressed in cultured human monocytes and differentiated osteoclasts. Western blot analysis detected a 55-kD ASIC2 protein in both membrane and cytoplasmic fractions of cultured human osteoblasts.

▼ Gene Function
Waldmann et al. (1996) found that MDEG was an amiloride-sensitive cation channel that was activated by the same mutations that cause neurodegeneration in C. elegans. MDEG did not induce detectable channel activity during expression in Xenopus oocytes or HEK293 cells.

Diochot et al. (2012) showed that a class of 3-finger peptides from the black mamba snake (Dendroaspis polylepis polylepis) is able to abolish pain through inhibition of ASICs expressed either in central or peripheral neurons. These peptides, which the authors called mambalgins, are not toxic in mice but show a potent analgesic effect upon central and peripheral injection that can be as strong as morphine. This effect is, however, resistant to naloxone, and mambalgins cause much less tolerance than morphine and no respiratory distress. Pharmacologic inhibition by mambalgins combined with the use of knockdown and knockout animals indicated that blockade of heteromeric channels made of ASIC1a and ASIC2a subunits in central neurons and of ASIC1b-containing channels in nociceptors is involved in the analgesic effect of mambalgins. Diochot et al. (2012) suggested that their findings identified potential therapeutic targets for pain and introduce natural peptides that block them to produce a potent analgesia.

▼ Mapping
Waldmann et al. (1996) used radioactive in situ hybridization to map the MDEG gene to human chromosome 17q11.2-q12.

▼ Animal Model
Price et al. (2000) generated mice deficient in Bnc1 by targeted disruption. Bnc1 -/- mice had markedly reduced sensitivity of a specific component of mechanosensation: low-threshold rapidly adapting mechanoreceptors. In rodent hairy skin these mechanoreceptors are excited by hair movement. Consistent with this function, Price et al. (2000) found Bnc1 in lanceolate nerve endings that lie adjacent to and surround the hair follicle. Although BCN1 had been proposed to have a role in pH sensing, Price et al. (2000) found that the acid-evoked current in cultured sensory neurons and the response of acid-stimulated nociceptors were normal in Bnc1-null mice. Price et al. (2000) concluded that their data identified the BNC1 channel as essential for the normal detection of light touch and indicated that BNC1 may be a central component of a mechanosensory complex.

Arterial baroreceptors are key regulators of arterial blood pressure, blood volume, and neurohumoral control of circulation. Baroreceptor somata are located in the nodose ganglia and petrosal ganglia, and their nerve endings project to the aortic arch and carotid sinus, respectively. Lu et al. (2009) found that Asic2 was highly expressed in most neurons of mouse nodose ganglia and their terminals. Asic2 -/- mice showed hypertension, exaggerated sympathetic control and depressed parasympathetic control of circulation, and decreased gain of the baroreceptor reflex. Multiple measurements of baroreceptor activity in Asic2 -/- mice suggested diminished baroreceptor mechanosensitivity.

Tags: 17q12, 17q11.2