Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

H(+)-gated cation channels are members of a new family of ionic channels, which includes the epithelial Na+ channel and the FMRFamide-activated Na+ channel. ASIC, the first member of the H(+)-gated Na+ channel subfamily, is expressed in brain and dorsal root ganglion cells (DRGs). It is activated by pHe variations below pH 7. The presence of this channel throughout the brain suggests that the H+ might play an essential role as a neurotransmitter or neuromodulator. The ASIC channel is also present in dorsal root ganglion cells, as is its homolog DRASIC, which is specifically present in DRGs and absent in the brain. Since external acidification is a major factor in pain associated with inflammation, hematomas, cardiac or muscle ischemia, or cancer, these two channel proteins are potentially central players in pain perception. ASIC activates and inactivates rapidly, while DRASIC has both a fast and sustained component. Other members of this family such as MDEG1 and MDEG2 are either H(+)-gated Na+ channels by themselves (MDEG1) or modulators of H(+)-gated channels formed by ASIC and DRASIC. MDEG1 is of particular interest because the same mutations that produce selective neurodegeneration in C. elegans mechanosensitive neurons, when introduced in MDEG1, also produce neurodegeneration. MDEG2 is selectively expressed in DRGs, where it assembles with DRASIC to radically change its biophysical properties, making it similar to the native H(+)-gated channel, which is presently the best candidate for pain perception.
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PMID:H(+)-gated cation channels. 1041 82

Acidosis is associated with inflammation and ischemia and activates cation channels in sensory neurons. Inflammation also induces expression of FMRFamidelike neuropeptides, which modulate pain. We found that neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe amide) and FMRFamide (Phe-Met-Arg-Phe amide) generated no current on their own but potentiated H+-gated currents from cultured sensory neurons and heterologously expressed ASIC and DRASIC channels. The neuropeptides slowed inactivation and induced sustained currents during acidification. The effects were specific; different channels showed distinct responses to the various peptides. These results suggest that acid-sensing ion channels may integrate multiple extracellular signals to modify sensory perception.
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PMID:Neuropeptide FF and FMRFamide potentiate acid-evoked currents from sensory neurons and proton-gated DEG/ENaC channels. 1079 98

Acid-sensing ion channel 3 (ASIC3) is highly expressed on sensory neurons that innervate heart and skeletal muscle and, therefore, is proposed to detect lactic acidosis and to transduce angina and muscle ischemic pain. A difficulty with this idea is that ASIC3 rapidly desensitizes. How can a desensitizing ion channel mediate a persisting sensation such as angina? Here, we show that rat ASIC3 produces a sustained current within the limited range of extracellular pH (7.3 to 6.7) that occurs during cardiac and skeletal muscle ischemia; experiments use patch clamp on transfected cell lines and on fluorescently tagged sensory neurons that innervate rat heart. No such sustained current occurs with ASIC1a (either as homomers or 1a/3 heteromers), whereas ASIC2a/3 heteromers give much larger currents than ASIC3 homomers. The sustained current persists even over tens of minutes because it is caused by a region of pH where there is overlap between inactivation and activation of the channel. Lactate, an anaerobic metabolite, allows the current to activate at slightly more basic pH. Surprisingly, amiloride, which blocks ASICs when they are activated at lower pH, increases ASIC3 current evoked at pH 7.0. Cardiac sensory neurons exhibit a small, perfectly sustained current when pH changes from 7.4 to 7.0. At least some of this current is carried by ASICs because the current is increased by both Zn(2+), an ASIC modulator, and amiloride. We suggest that this sustained mode is the most relevant form of ASIC3 gating for triggering angina and other ischemic pain.
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PMID:Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial ischemia. 1694 38

Acid-sensing ion channel 3 (ASIC3) is the most sensitive acid sensor in sensory neurons that innervate into skin, muscle, heart, and visceral tissues. ASIC3 is involved in ischemia sensing, nociception, mechanosensation, and hearing, but how ASIC3-expressing neurons differ in their firing properties is still unknown. We hypothesized that ASIC3-expressing neurons have specialized firing properties, which, coupled with the heterogeneity of acid-sensing properties, accounts for various physiological roles. Here, we successfully identified ASIC3-expressing lumbar dorsal root ganglion (DRG) neurons whose transient proton-gated currents were blocked by salicylic acid (SA). The salicylic acid-sensitive (SAS) neurons did not exist in DRG neurons of mice lacking ASIC3. SAS neurons expressed distinct electrophysiological properties as compared with other DRG neurons. Especially, SAS neurons fired action potentials (APs) with large overshoot and long afterhyperpolarization duration, which suggests that they belong to nociceptors. SAS neurons also exhibited multiple nociceptor markers such as capsaicin response (38%), action potential (AP) with inflection (35%), or tetrodotoxin resistance (31%). Only in SAS neurons but not other DRG neurons was afterhyperpolarization duration correlated with resting membrane potential and AP duration. Our studies reveal a unique feature of ASIC3-expressing DRG neurons and a basis for their heterogeneous functions.
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PMID:Identification and characterization of a subset of mouse sensory neurons that express acid-sensing ion channel 3. 1808 72

Acid-sensing ion channel 3 (ASIC3) is a proton-gated, voltage-insensitive Na(+) channel that is expressed primarily in peripheral sensory neurons and plays an important role in pain perception, particularly as a pH sensor following cardiac ischemia. We previously reported that ASIC3 currents are not affected by zinc at nanomolar concentrations. In this study, we examined the potential role of micromolar zinc in the regulation of ASIC3. In CHO cells expressing ASIC3, we found that ASIC3 currents triggered by dropping the pH from 7.4 to 6.0 were inhibited by pretreatment with zinc in a concentration-dependent manner; the half-maximum inhibitory concentration of zinc was 61 muM. ASIC currents activated by a relatively small drop in pH from 7.4 to 7.2 or 7.0 were also subject to inhibition by zinc. The inhibition was fast and pH independent, and occurred within a relatively narrow range of zinc concentrations between 30 and 300 muM. Further, increasing extracellular Ca(2+) concentrations from 2 to 10 mM failed to affect inhibition of ASIC3 currents by zinc. Experimentally elevating intracellular zinc levels did not affect the inhibition of ASIC3 currents by equal concentrations of extracellular zinc, and modification of cysteine or histidine residues had no effect on the inhibition of ASIC3 currents by zinc. These collective results suggest that zinc is an important regulator of ASIC3 at physiological concentrations, that zinc inhibits ASIC3 in a pH- and Ca(2+)-independent manner, and that inhibition of ASIC3 currents is dependent upon the interaction of zinc with extracellular domain(s) of ASIC3.
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PMID:Inhibitory regulation of acid-sensing ion channel 3 by zinc. 2058 Jul 86