Acid-sensing (proton-gated) ion channels (ASICs) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [35]) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and 'orphan' channels that include BLINaC [46] and INaC [47] that have also been named BASICs, for bile acid-activated ion channels [58]. ASIC subunits contain two TM domains and assemble as homo- or hetero-trimers [34, 31, 5] to form proton-gated, voltage-insensitive, Na+ permeable, channels (reviewed in [33, 57]). Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [55], ASIC1b (ASICβ, BNaC2β) [13] and ASIC1b2 (ASICβ2) [50]; note that ASIC1a is also permeable to Ca2+] and ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [45, 56, 30] and ASIC2b (MDEG2, BNaC1β) [40]] have been cloned. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [54], has been identified. A fourth mammalian member of the family (ASIC4/SPASIC) does not support a proton-gated channel in heterologous expression systems and is reported to downregulate the expression of ASIC1a and ASIC3 [1, 32, 24, 39]. ASIC channels are primarily expressed in central and peripheral neurons including nociceptors where they participate in neuronal sensitivity to acidosis. They have also been detected in taste receptor cells (ASIC1-3), photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [25, 36, 63], responses to focal ischemia [59] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [29], as well as seizures [64] and pain [19, 20, 10, 22]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [40, 3, 28, 8].

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Acid-sensing (proton-gated) ion channels (ASICs) in GtoPdb v.2021.3

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f118/2021.3 ◽

2021 ◽

Vol 2021 (3) ◽

Author(s):

Stephan Kellenberger ◽

Lachlan D. Rash

Keyword(s):

Ion Channels ◽

Heterologous Expression ◽

Splice Variants ◽

Ion Selectivity ◽

Taste Receptor ◽

Lung Epithelial Cells ◽

Na Channel ◽

Cochlear Hair Cells ◽

Peripheral Neurons ◽

Heterologous Expression Systems

Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [45, 2, 3]) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and 'orphan' channels that include BLINaC [66] and INaC [68] that have also been named BASICs, for bile acid-activated ion channels [86]. ASIC subunits contain 2 TM domains and assemble as homo- or hetero-trimers [43, 40, 7, 90, 89, 73] to form proton-gated, voltage-insensitive, Na+ permeable, channels that are activated by levels of acidosis occurring in both physiological and pathophysiological conditions with ASIC3 also playing a role in mechanosensation (reviewed in [42, 85, 45, 65, 23]) . Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [80], ASIC1b (ASICβ, BNaC2β) [19] and ASIC1b2 (ASICβ2) [75]; note that ASIC1a is also permeable to Ca2+] and ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [63, 81, 39] and ASIC2b (MDEG2, BNaC1β) [53]] have been cloned and differ in the first third of the protein. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [79] is one of the most pH-sensitive isoforms (along with ASIC1a) and has the fastest activation and desensitisation kinetics, however can also carry small sustained currents. ASIC4 (SPASIC) evolved as a proton-sensitive channel but seems to have lost this function in mammals [55]. Mammalian ASIC4 does not support a proton-gated channel in heterologous expression systems but is reported to downregulate the expression of ASIC1a and ASIC3 [1, 41, 33, 51]. ASIC channels are primarily expressed in central (ASIC1a, -2a, 2b and -4) and peripheral neurons including nociceptors (ASIC1-3) where they participate in neuronal sensitivity to acidosis. They have also been detected in taste receptor cells (ASIC1-3)), photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3) (ASIC distribution is well reviewed in [52, 27]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [34, 47, 93], responses to focal ischemia [87] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [38], as well as seizures [94] and pain [85, 28, 29, 13, 31]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [53, 5, 37, 11]. In general, the known small molecule inhibitors of ASICs are non-selective or partially selective, whereas the venom peptide inhibitors have substantially higher selectivity and potency. Several clinically used drugs are known to inhibit ASICs, however they are generally more potent at other targets (e.g. amiloride at ENaCs, ibuprofen at COX enzymes) [64, 60]. The information in the tables below are for the effects of inhibitors on homomeric channels, for information of known effect on heteromeric channels see the comments below.

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Acid-sensing (proton-gated) ion channels (ASICs) (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f118/2020.5 ◽

2020 ◽

Vol 2020 (5) ◽

Author(s):

Stephan Kellenberger ◽

Lachlan D. Rash

Keyword(s):

Ion Channels ◽

Heterologous Expression ◽

Splice Variants ◽

Ion Selectivity ◽

Taste Receptor ◽

Lung Epithelial Cells ◽

Na Channel ◽

Cochlear Hair Cells ◽

Peripheral Neurons ◽

Heterologous Expression Systems

Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [43, 2, 3]) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and 'orphan' channels that include BLINaC [62] and INaC [64] that have also been named BASICs, for bile acid-activated ion channels [81]. ASIC subunits contain two TM domains and assemble as homo- or hetero-trimers [41, 38, 7] to form proton-gated, voltage-insensitive, Na+ permeable, channels that are activated by levels of acidosis occurring in both physiological and pathophysiological conditions with ASIC3 also playing a role in mechanosensation (reviewed in [40, 80, 43, 61, 21]) . Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [75], ASIC1b (ASICβ, BNaC2β) [17] and ASIC1b2 (ASICβ2) [70]; note that ASIC1a is also permeable to Ca2+] and ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [59, 76, 37] and ASIC2b (MDEG2, BNaC1β) [51]] have been cloned and differ in the first third of the protein. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [74] is one of the most pH-sensitive isoforms (along with ASIC1a) and has the fastest activation and desensitisation kinetics, however can also carry small sustained currents. ASIC4 (SPASIC) evolved as a proton-sensitive channel but seems to have lost this function in mammals [52]. Mammalian ASIC4 does not support a proton-gated channel in heterologous expression systems but is reported to downregulate the expression of ASIC1a and ASIC3 [1, 39, 31, 49]. ASIC channels are primarily expressed in central (ASIC1a, -2a, 2b and -4) and peripheral neurons including nociceptors (ASIC1-3) where they participate in neuronal sensitivity to acidosis. They have also been detected in taste receptor cells (ASIC1-3)), photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3) (ASIC distribution is well reviewed in [50, 25]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [32, 45, 87], responses to focal ischemia [82] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [36], as well as seizures [88] and pain [80, 26, 27, 13, 29]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [51, 5, 35, 11]. In general, the known small molecule inhibitors of ASICs are non-selective or partially selective, whereas the venom peptide inhibitors have substantially higher selectivity and potency. Several clinically used drugs are known to inhibit ASICs, however they are generally more potent at other targets (e.g. amiloride at ENaCs, ibuprofen at COX enzymes) [60, 56]. The information in the tables below are for the effects of inhibitors on homomeric channels, for information of known effect on heteromeric channels see the comments below.

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Heterologous Expression Systems and Analyses of Ion Channels

Springer Protocols Handbooks - Patch Clamp Techniques ◽

10.1007/978-4-431-53993-3_23 ◽

2012 ◽

pp. 353-370 ◽

Cited By ~ 1

Author(s):

Kazuharu Furutani ◽

Yoshihisa Kurachi

Keyword(s):

Ion Channels ◽

Heterologous Expression ◽

Expression Systems ◽

Heterologous Expression Systems

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Functional Characterization of Plant Ion Channels in Heterologous Expression Systems

Plant Electrophysiology ◽

10.1007/978-3-642-29119-7_13 ◽

2012 ◽

pp. 301-321 ◽

Cited By ~ 2

Author(s):

Yi Wang

Keyword(s):

Ion Channels ◽

Heterologous Expression ◽

Functional Characterization ◽

Expression Systems ◽

Heterologous Expression Systems ◽

Plant Ion Channels

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Congenital Deletion of Nedd4-2 in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22116146 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6146

Author(s):

Dominik H. W. Leitz ◽

Julia Duerr ◽

Surafel Mulugeta ◽

Ayça Seyhan Agircan ◽

Stefan Zimmermann ◽

...

Keyword(s):

Epithelial Cells ◽

Pulmonary Fibrosis ◽

Growth Failure ◽

Lung Epithelial Cells ◽

Na Channel ◽

Preclinical Development ◽

Neonatal Mice ◽

Mucin Expression ◽

Lung Epithelial ◽

The Impact

Recent studies found that expression of Nedd4‑2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of Nedd4‑2 in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na+ channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of Nedd4‑2 on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of Nedd4‑2 in the lung epithelial cells of neonatal doxycycline-induced triple transgenic Nedd4‑2fl/fl/CCSP‑rtTA2S‑M2/LC1 mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP‑C trafficking. We found that the congenital deletion of Nedd4‑2 caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of Nedd4‑2 in lung epithelial cells caused increased expression of Muc5b and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of Nedd4‑2 may support studies of the pathogenesis and preclinical development of therapies for chILD.

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Kv3.1–Kv3.2 Channels Underlie a High-Voltage–Activating Component of the Delayed Rectifier K+ Current in Projecting Neurons From the Globus Pallidus

Journal of Neurophysiology ◽

10.1152/jn.1999.82.3.1512 ◽

1999 ◽

Vol 82 (3) ◽

pp. 1512-1528 ◽

Cited By ~ 64

Author(s):

R. Hernández-Pineda ◽

A. Chow ◽

Y. Amarillo ◽

H. Moreno ◽

M. Saganich ◽

...

Keyword(s):

Heterologous Expression ◽

Globus Pallidus ◽

High Frequency ◽

Calcium Binding ◽

Repetitive Firing ◽

Delayed Rectifier ◽

Expression Systems ◽

Electrophysiological Properties ◽

Channel Proteins ◽

Heterologous Expression Systems

The globus pallidus plays central roles in the basal ganglia circuitry involved in movement control as well as in cognitive and emotional functions. There is therefore great interest in the anatomic and electrophysiological characterization of this nucleus. Most pallidal neurons are GABAergic projecting cells, a large fraction of which express the calcium binding protein parvalbumin (PV). Here we show that PV-containing pallidal neurons coexpress Kv3.1 and Kv3.2 K+ channel proteins and that both Kv3.1 and Kv3.2 antibodies coprecipitate both channel proteins from pallidal membrane extracts solubilized with nondenaturing detergents, suggesting that the two channel subunits are forming heteromeric channels. Kv3.1 and Kv3.2 channels have several unusual electrophysiological properties when expressed in heterologous expression systems and are thought to play special roles in neuronal excitability including facilitating sustained high-frequency firing in fast-spiking neurons such as interneurons in the cortex and the hippocampus. Electrophysiological analysis of freshly dissociated pallidal neurons demonstrates that these cells have a current that is nearly identical to the currents expressed by Kv3.1 and Kv3.2 proteins in heterologous expression systems, including activation at very depolarized membrane potentials (more positive than −10 mV) and very fast deactivation rates. These results suggest that the electrophysiological properties of native channels containing Kv3.1 and Kv3.2 proteins in pallidal neurons are not significantly affected by factors such as associated subunits or postranslational modifications that result in channels having different properties in heterologous expression systems and native neurons. Most neurons in the globus pallidus have been reported to fire sustained trains of action potentials at high-frequency. Kv3.1–Kv3.2 voltage-gated K+channels may play a role in helping maintain sustained high-frequency repetitive firing as they probably do in other neurons.

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The determination of the ion selectivity of synthetic ion channels and pores in vesicles

Journal of Physical Organic Chemistry ◽

10.1002/poc.1047 ◽

2006 ◽

Vol 19 (8-9) ◽

pp. 452-460 ◽

Cited By ~ 44

Author(s):

Naomi Sakai ◽

Stefan Matile

Keyword(s):

Ion Channels ◽

Ion Selectivity ◽

Synthetic Ion Channels

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Molecular mechanisms of taste transduction

Pure and Applied Chemistry ◽

10.1351/pac200274071125 ◽

2002 ◽

Vol 74 (7) ◽

pp. 1125-1133 ◽

Cited By ~ 6

Author(s):

Robert F. Margolskee

Keyword(s):

Ion Channels ◽

Molecular Cloning ◽

G Proteins ◽

Molecular Mechanisms ◽

Transmembrane Helix ◽

Taste Receptor ◽

Sweet Taste ◽

Chemical Diversity ◽

Chemical Information ◽

Taste Transduction

Taste transduction is a specialized form of signal transduction by which taste receptor cells (TRCs) encode at the cellular level information about chemical substances encountered in the oral environment (so-called tastants). Bitter and sweet taste transduction pathways convert chemical information into a cellular second messenger code utilizing cyclic nucleotides, inositol trisphosphate, and/or diacyl glycerol. These messengers are components of signaling cascades that lead to TRC depolarization and Ca++ release. Bitter and sweet taste transduction pathways typically utilize taste-specific or taste-selective seven transmembrane-helix receptors, G proteins, effector enzymes, second messengers, and ion channels. The structural and chemical diversity of tastants has led to the need for multiple transduction mechanisms. Through molecular cloning and data mining, many of the receptors, G proteins, and effector enzymes involved in transducing responses to bitter and sweet compounds are now known. New insights into taste transduction and taste coding underlying sweet and bitter taste qualities have been gained from molecular cloning of the transduction elements, biochemical elucidation of the transduction pathways, electrophysiological analysis of the function of taste cell ion channels, and behavioral analysis of transgenic and knockout models.

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