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ASIC2a and ASIC3 heteromultimerize to form pH-sensitive channels in mouse cardiac dorsal root ganglia neurons.

ABSTRACT: Acid-sensing ion channels (ASICs) are Na+ channels that are activated by acidic pH. Their expression in cardiac afferents and remarkable sensitivity to small pH changes has made them leading candidates to sense cardiac ischemia.Four genes encode six different ASIC subunits, however it is not yet clear which of the ASIC subunits contribute to the composition of ASICs in cardiac afferents.Here, we labeled cardiac afferents using a retrograde tracer dye in mice, which allowed for patch-clamp studies of murine cardiac afferents. We found that a higher percentage of cardiac sensory neurons from the dorsal root ganglia respond to acidic pH and generated larger currents compared to those from the nodose ganglia. The ASIC-like current properties of the cardiac dorsal root ganglia neurons from wild-type mice most closely matched the properties of ASIC2a/3 heteromeric channels. This was supported by studies in ASIC-null mice: acid-evoked currents from ASIC3(-/-) cardiac afferents matched the properties of ASIC2a channels, and currents from ASIC2(-/-) cardiac afferents matched the properties of ASIC3 channels.We conclude that ASIC2a and -3 are the major ASIC subunits in cardiac dorsal root ganglia neurons and provide potential molecular targets to attenuate chest pain and deleterious reflexes associated with cardiac disease.

SUBMITTER: Hattori T

PROVIDER: S-EPMC4472433 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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ASIC2a and ASIC3 heteromultimerize to form pH-sensitive channels in mouse cardiac dorsal root ganglia neurons.

Hattori Tomonori T Chen Jie J Harding Anne Marie S AM Price Margaret P MP Lu Yongjun Y Abboud Francois M FM Benson Christopher J CJ

Circulation research 20090709 3

<h4>Rationale</h4>Acid-sensing ion channels (ASICs) are Na+ channels that are activated by acidic pH. Their expression in cardiac afferents and remarkable sensitivity to small pH changes has made them leading candidates to sense cardiac ischemia.<h4>Objective</h4>Four genes encode six different ASIC subunits, however it is not yet clear which of the ASIC subunits contribute to the composition of ASICs in cardiac afferents.<h4>Methods and results</h4>Here, we labeled cardiac afferents using a ret ...[more]

PMID: 19590043

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Project description:BackgroundPostherpetic neuralgia (PHN) is a devastating complication after varicella-zoster virus infection. Brain-derived neurotrophic factor (BDNF) has been shown to participate in the pathogenesis of PHN. A truncated isoform of the tropomyosin receptor kinase B (TrkB) receptor TrkB.T1, as a high-affinity receptor of BDNF, is upregulated in multiple nervous system injuries, and such upregulation is associated with pain. Acid-sensitive ion channel 3 (ASIC3) is involved in chronic neuropathic pain, but its relation with BDNF/TrkB.T1 in the peripheral nervous system (PNS) during PHN is unclear. This study aimed to investigate whether BDNF/TrkB.T1 contributes to PHN through regulating ASIC3 signaling in dorsal root ganglia (DRGs).MethodsResiniferatoxin (RTX) was used to induce rat PHN models. Mechanical allodynia was assessed by measuring the paw withdrawal thresholds (PWTs). Thermal hyperalgesia was determined by detecting the paw withdrawal latencies (PWLs). We evaluated the effects of TrkB.T1-ASIC3 signaling inhibition on the behavior, neuronal excitability, and inflammatory response during RTX-induced PHN. ASIC3 short hairpin RNA (shRNA) transfection was used to investigate the effect of exogenous BDNF on inflammatory response in cultured PC-12 cells.ResultsRTX injection induced mechanical allodynia and upregulated the protein expression of BDNF, TrkB.T1, ASIC3, TRAF6, nNOS, and c-Fos, as well as increased neuronal excitability in DRGs. Inhibition of ASIC3 reversed the abovementioned effects of RTX, except for BDNF and TrkB.T1 protein expression. In addition, inhibition of TrkB.T1 blocked RTX-induced mechanical allodynia, activation of ASIC3 signaling, and hyperexcitability of neurons. RTX-induced BDNF upregulation was found in both neurons and satellite glia cells in DRGs. Furthermore, exogenous BDNF activated ASIC3 signaling, increased NO level, and enhanced IL-6, IL-1β, and TNF-α levels in PC-12 cells, which was blocked by shRNA-ASIC3 transfection.ConclusionThese findings demonstrate that inhibiting BDNF/TrkB.T1 reduced inflammation, decreased neuronal hyperexcitability, and improved mechanical allodynia through regulating the ASIC3 signaling pathway in DRGs, which may provide a novel therapeutic target for patients with PHN.

Dataset Information

ASIC2a and ASIC3 heteromultimerize to form pH-sensitive channels in mouse cardiac dorsal root ganglia neurons.

Publications

ASIC2a and ASIC3 heteromultimerize to form pH-sensitive channels in mouse cardiac dorsal root ganglia neurons.

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