Previous studies suggest that there might be close relationship between acid. Significant progress has been made in understanding the structure and function of asics at the molecular level. Acidsensing ion channels in acidosisinduced injury of. Acidsensing ion channels asics are a group of amiloridesensitive ligandgated ion channels belonging to the family of degenerinepithelial sodium channels.
A decrease in ph may be due to a variety of reasons including tissue inflammation, ischemic stroke, an accumulation of lactic acid due to increased cellular metabolism. P2x receptors and acidsensing ion channels asics are trimeric membrane ion channels gated by binding extracellular ligands. Asics are members of the degenerinepithelial sodium ion channel degenac family, a group of voltageinsensitive cation channels expressing in the nervous system and many types of epithelial cells and immune cells fig. However, whether asic1a also contributes to pain perception at the supraspinal level remains elusive. Increasing evidence suggests that asics represent essential sensors for tissue acidosisrelated pain. Protein kinase c lambda mediates acidsensing ion channel. Pore architecture and ion sites in acidsensing ion. Acidsensing ion channels asics are protongated ion channels broadly expressed in the vertebrate nervous system, converting decreased extracellular ph into excitatory sodium current.
Acid sensing ion channels asics are trimeric 1, protongated 2,3 and sodiumselective 4,5 members of the epithelial sodium channeldegenerin enacdeg superfamily of ion channels 6,7 and are. Acid sensing ion channel 2 asic2 also known as amiloridesensitive cation channel 1, neuronal accn1 or brain sodium channel 1 bnac1 is a protein that in humans is encoded by the asic2 gene. Abstractaccording to a modern look acidsensing ion channels asics are one of the most important receptors that per ceive ph change in the body. Acidsensing ion channels asics are protongated sodiumselective channels that are expressed in the peripheral and central nervous systems.
Acidsensing ion channels asics are trimeric 1, protongated 2,3 and sodiumselective 4,5 members of the epithelial sodium channeldegenerin enacdeg superfamily of. Aug 14, 2018 acid sensing ion channels asics are protongated ion channels broadly expressed in the vertebrate nervous system, converting decreased extracellular ph into excitatory sodium current. Asics are predominantly expressed in both the peripheral and central nervous system and have been characterized as potent proton sensors to detect extracellular acidification in the periphery and brain. Diochot s, baron a, salinas m, douguet d, scarzello s, dabertgay as, debayle d, friend v, alloui a, lazdunski m, lingueglia e 2012 black mamba venom peptides target acidsensing ion channels to abolish pain. In central and peripheral neurons, acidsensing ion channels asics have emerged as key receptors for extracellular protons, and recent studies suggest diverse roles for these channels in the pathophysiology of. The asic2 gene is one of the five paralogous genes that encode proteins that form trimeric acid sensing ion channels asics in mammals. Asics have also been implicated in mechanosensation in the peripheral. In central and peripheral neurons, acid sensing ion channels asics have emerged as key receptors for extracellular protons, and recent studies suggest diverse roles for these channels in the pathophysiology of pain, ischemic stroke and psychiatric disease. Ho f c y t o logy i a l st r n olg journal of cytology. High doses of salicylate and aspirin are inhibitory on acid. Acid sensing ion channels asics are trimeric 1, protongated 2,3 and sodiumselective 4,5 members of the epithelial sodium channel degenerin enacdeg superfamily of ion channels 6,7 and are. Derived from 5 genes accn15, 7 subunits have been identified, 1a, 1b, 2a, 2b, 3, 4, and 5, that are widely expressed in the peripheral and central nervous system as well as other tissues. Chronic pain is a serious debilitating disease for which effective treatment is still lacking.
Asics were previously thought to be a vertebratespecific branch of the degenac family, a broadly conserved but functionally diverse family of channels. Pdf acidsensing ion channels in postoperative pain. Acid sensing ion channel 1a asic1a has been implicated in nociceptive processing at both peripheral and spinal neurons. Mice without neuronal asic1 and asic2 have reduced response to the predator odor. Conserved hisgly motif of acidsensing ion channels resides. Acid sensing ion channels asics are a group of amiloridesensitive ligandgated ion channels belonging to the family of degenerinepithelial sodium channels. In the present study, we identified the existence of asics in the primary cultured rat microglia and explored their functions. Ion channels in immunology research t and b cells and microglia express a wide variety of ion channels, which are implicated in immune processes. Acid sensing ion channels are abundantly expressed in neurons, but little is known regarding the potential impact of acid sensing ion channels on the cerebral circulation, particularly in the microcirculation. Carver college of medicine, university of iowa, iowa city, ia 52242, usa. One of the pathways is targeting neuronal receptorsion channels in the central nervous system. Acidsensing ion channels asics, provisional nomenclature.
These genes have splice variants that encode for several isoforms that are marked by a suffix. Acidactivated currents blocked by amiloride have been reported for a long time in most neurons of the mammalian brain as well as in sensory neurons. A decade ago, waldmann and colleagues were the first to clone the ion channels underlying these currents, which have been called acid sensing ion channels asics. Acid sensing ion channels asics are protongated sodiumselective channels that are expressed in the peripheral and central nervous systems. Apetx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on asic3 has impeded development of improved analogues. Correspondingly, increasing evidence has implicated acid. Here we characterized asiclike currents in dorsal horn neurons of the rat spinal cord and their functional modulation in pathological conditions. Multiple pathways are responsible for the therapeutic actions exerted by these drugs. Acidsensing ion channels asics, also known as accns are voltageindependent, sodiumselective, ligandgated ion channels expressed in. An overview of the acidsensing ion channels acidsensitive ion currents were first reported in sensory neurons,11 and it has been known that the acidsensing ion channels.
Acidevoked currents were first observed in neurons in the early 1980s 1,2. To elucidate this topic in fishes we have systematically investigated the occurrence of different ion channels involved in chemodetection in mammals acidsensing ion channels 1 to 4 asic 14. Acid sensing protongated ion channels asics and epithelial sodium channels enacs the recently discovered enacdegenerin gene family encodes sodium channels involved in various cell functions in metazoans. Extracellular acid can have important effects on neuron function. Acidsensing ion channels in sensory perception request pdf. Acid sensing ion channel 2 asic2 works as a protongated ion channel. Increasing evidence has identified two principal types of protongated channels. The acid sensing ion channel asic family contains six subunits asic1a, asic1b, asic2a, asic2b, asic3 and asic4 encoded by four genes asic14 85,86. Editorial full text access acidsensing ion channels in the nervous system.
Acidsensing ion channels in the nervous system sciencedirect. Acid sensing ion channels asics can detect a broad range of physiological ph changes during pathological and synaptic cellular activities. The sea anemone peptide apetx2 is a potent and selective blocker of acidsensing ion channel 3 asic3. In the central nervous system, asic2 was detected in neurons. Acidsensing ion channels as potential therapeutic targets in. Asic proteins are a subfamily of the enac deg superfamily of ion channels.
To elucidate this topic in fishes we have systematically investigated the occurrence of different ion channels involved in chemodetection in mammals acid sensing ion channels 1 to 4 asic 14. A decade ago, waldmann and colleagues were the first to clone the ion channels underlying these currents, which have been called acidsensing ion channels asics. Rosen, in reference module in neuroscience and biobehavioral psychology, 2017. Gating mechanisms of acidsensing ion channels nature. Asics are voltageindependent, protongated cation channels widely expressed throughout the central and peripheral nervous system. Conserved hisgly motif of acidsensing ion channels. Carattino1,2 and x nicolas montalbetti1 1renalelectrolyte division, department of medicine, university of pittsburgh, pittsburgh, pennsylvania. In 1997, a protein producing a similar acidgated current was cloned and identified as an acidsensing ion channel asic 3.
Reverse transcriptasepcr and western blot detected a high level of the asic1a subunit with little or. In disease states, tissue acidosis is a common pathologic change causing abnormal activation of acidsensing ion channels asics, which according to cumulative evidence, significantly contributes to inflammation, mitochondrial dysfunction, and other pathologic mechanisms i. Asics belong to a superfamily which also contains degenerins deg and epithelial sodium channels enac. Our previous report showed that asic2 was expressed in ciliated and stereociliated cells. Acidsensing ion channels in human cortical neurons show electrophysiological and pharmacological properties distinct from those in neurons of the rodent brain. Acid sensing ion channels asic are observed to be activated at phs under 6 with variability depending on the type of channel and its location. Acidsensing ion channel an overview sciencedirect topics. Acid sensing ion channels in human cortical neurons show electrophysiological and pharmacological properties distinct from those in neurons of the rodent brain. According to a modern look acidsensing ion channels asics are one of the most important receptors that perceive ph change in the body. Asics act as proton sensors in the nervous system where they contribute, besides other roles, to fear behaviour, learning and pain sensation. Acid sensing ion channels asics are members of the epithelial sodium channel enacdegenerin deg family, characterized by two transmembrane domains and a large cysteinerich extracellular domain. The etiology and pathophysiology of postoperative pain are still poorly understood, but hydrogen ions appear to be important in this process.
Here, we report that asic1a in acc is required for thermal and mechanical. Abstract acid sensing ion channels asics are cationselective membrane channels activated by h1 binding upon decrease in extracellular ph. Acidsensing ion channels asics are a family of protongated cation channels which are expressed primarily in the nervous system 1, 2. Iatrogenic pain consecutive to a large number of surgical procedures has become a growing health concern.
Carver college of medicine, university of iowa, iowa city, ia 52242, usa 2department of veterans affairs medical center, iowa city, ia 52242, usa 3department of internal medicine, roy j. Acid sensing ion channels asics are protongated members of the epithelial sodium channeldegenerin enacdeg superfamily of ion channels and are expressed throughout central and peripheral nervous systems. Asic1a is one of the most intensively studied isoforms due to its importance and wide representation in organisms, but it is still largely unexplored as a target for therapy. Asic1a functions as the mediator for cells in nucleus pulposus np and endplate ep, with whose. Characterization of acidsensing ion channels in dorsal. However, ciliated ependymal cells also expressed asic2. Understanding the molecular basis of toxin promiscuity.
Pore architecture and ion sites in acidsensing ion channels. Potentiation of acidsensing ion channels by sulfhydryl compounds junhyeong cho and candice c. Potentiation of acidsensing ion channels by sulfhydryl compounds. Characterization of acidsensing ion channels in dorsal horn. Structure and activity of the acidsensing ion channels thomas w. Structure and activity of the acidsensing ion channels. Acidsensing ion channels are abundantly expressed in neurons, but little is known regarding the potential impact of acidsensing ion channels on the cerebral circulation, particularly in the microcirculation.
In periphery, they contribute to sensory transmission, including that of nociception and pain. Here we present a detailed structureactivity relationship study of apetx2. High doses of salicylate and aspirin are inhibitory on. Acidsensing ion channels as potential therapeutic targets. In large part, this question has driven increasing investigation on acid sensing ion channels asics in the cns and the peripheral nervous system for the past two decades. Askwith department of neuroscience, the ohio state university wexner medical center, columbus, ohio. Optical control of trimeric p2x receptors and acidsensing. The function and regulation of acidsensing ion channels. It is known that ca21 plays an important modulatory role in asic gating, competing with the ligand h 1foritsbindingsites.
Jul 04, 2014 acid sensing ion channel forms a homotrimer. Acidsensing protongated ion channels asics and epithelial sodium channels enacs the recently discovered enacdegenerin gene family encodes sodium channels involved in. Acidsensing ion channel 2 asic2 also known as amiloridesensitive cation channel 1, neuronal accn1 or brain sodium channel 1 bnac1 is a protein that in humans is encoded by the asic2 gene. According to a modern look acid sensing ion channels asics are one of the most important receptors that perceive ph change in the body. In disease states, tissue acidosis is a common pathologic change causing abnormal activation of acid sensing ion channels asics, which according to cumulative evidence, significantly contributes to inflammation, mitochondrial dysfunction, and other pathologic mechanisms i. Acidsensing ion channels mediate the degeneration of. Asic4, for which no channel activity has yet been demonstrated, shows a more dispersed expression in the cns linet al. May 30, 2015 maintaining the physiological ph of interstitial fluid is crucial for normal cellular functions. Acidsensing ion channels asics are members of the epithelial sodium channel enacdegenerin deg family, characterized by two transmembrane domains and a large cysteinerich extracellular domain. Acidsensing ion channels asics were once reported to be able to regulate the apoptosis process of chondrocytes in joint cartilage, which has been transplanted into the ivddrelated research. Below is a selection of compounds from tocris that may be used to explore the role of ion channels in the immune system. P2x receptors are gated by extracellular atp, and their physiological roles include neuroeffector transmission, primary afferent transmission e. The homotrimeric splice variant asic1a has been implicated in nociception, fear memory, mood disorders and ischemia.
Acidsensing ion channels basic information on asics physiological and pathological roles of asics. Activation of asics is involved in pain continue reading. Acidsensing ion channels asics can detect a broad range of physiological ph changes during pathological and synaptic cellular activities. Potentiation of acidsensing ion channels by sulfhydryl. Review acid sensing ion channels in sensory signaling x marcelo d. Maintaining the physiological ph of interstitial fluid is crucial for normal cellular functions. Askwith department of neuroscience, the ohio state university, columbus, ohio submitted 1 december 2006.
Potentiation of acidsensing ion channels by sulfhydrylcompounds. Acidsensing ion channels in acidosisinduced injury of human. Acid sensing ion channels asics are ligandgated cation channels activated by extracellular protons. The asic2 gene is one of the five paralogous genes that encode proteins that form trimeric acidsensing ion channels asics in mammals. Acidsensing ion channels asics are ligandgated cation channels activated by extracellular protons. Multiple modulation of acidsensing ion channel 1a by the. Jan 07, 2014 p2x receptors and acidsensing ion channels asics are trimeric membrane ion channels gated by binding extracellular ligands. Jul 30, 2009 acid sensing ion channels asics, also known as accns are voltageindependent, sodiumselective, ligandgated ion channels expressed in diverse organisms 1,2,3, and are members of the epithelial. Pdf acidsensing ion channels and pain researchgate. Structure and activity of the acid sensing ion channels thomas w. In rodents and humans, four genes, including accn1, accn2, accn3, and accn4, encoding at least six asic subtypes asic1a, asic1b, asic2a. Each protomer has two transmembrane regions, one at the n terminus and the other at the c terminus. Acidsensing ion channels asics are protongated members of the epithelial sodium channeldegenerin enacdeg superfamily of ion channels and are expressed throughout central and peripheral nervous systems.
959 1005 1319 106 1631 1613 1389 693 1051 762 1429 266 57 324 887 1236 625 1391 1125 1353 1002 1399 1607 304 578 1461 1137 841 174 939 1039 1076 2 753 708 1120 434 1437 237 299 1157 465 16