ASIC2a-dependent increase of ASIC3 surface expression enhances the sustained component of the currents

Kweon, Hae-Jin; Cho, Jin-Hwa; Jang, Il‐Sung; Suh, Byung‐Chang

doi:10.5483/bmbrep.2016.49.10.057

“…We also investigated the ability of mASIC3 and nmrASIC3 to form heteromers with rASIC2a and found that as shown previously ( 7 , 43 ) coexpression of mASIC3 and rASIC2a resulted in currents with an I sus / I peak that was significantly greater than that produced by either mASIC3 or rASIC2a homomers (mASIC3 + rASIC2a: 141 ± 25, n = 13 versus mASIC3: 48 ± 4%, n = 23, p < 0.001 and rASIC2a 29 ± 6%, n = 8, p < 0.001, Fig. 4 , A and D ).…”

Section: Resultssupporting

confidence: 73%

Naked mole-rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers

Schuhmacher¹,

Callejo²,

Srivats³

et al. 2018

Journal of Biological Chemistry

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Acid-sensing ion channels (ASICs) form both homotrimeric and heterotrimeric ion channels that are activated by extracellular protons and are involved in a wide range of physiological and pathophysiological processes, including pain and anxiety. ASIC proteins can form both homotrimeric and heterotrimeric ion channels. The ASIC3 subunit has been shown to be of particular importance in the peripheral nervous system with pharmacological and genetic manipulations demonstrating a role in pain. Naked mole-rats, despite having functional ASICs, are insensitive to acid as a noxious stimulus and show diminished avoidance of acidic fumes, ammonia, and carbon dioxide. Here we cloned naked mole-rat ASIC3 (nmrASIC3) and used a cell-surface biotinylation assay to demonstrate that it traffics to the plasma membrane, but using whole-cell patch clamp electrophysiology we observed that nmrASIC3 is insensitive to both protons and the non-proton ASIC3 agonist 2-guanidine-4-methylquinazoline. However, in line with previous reports of ASIC3 mRNA expression in dorsal root ganglia neurons, we found that the ASIC3 antagonist APETx2 reversibly inhibits ASIC-like currents in naked mole-rat dorsal root ganglia neurons. We further show that like the proton-insensitive ASIC2b and ASIC4, nmrASIC3 forms functional, proton-sensitive heteromers with other ASIC subunits. An amino acid alignment of ASIC3s between 9 relevant rodent species and human identified unique sequence differences that might underlie the proton insensitivity of nmrASIC3. However, introducing nmrASIC3 differences into rat ASIC3 (rASIC3) produced only minor differences in channel function, and replacing the nmrASIC3 sequence with that of rASIC3 did not produce a proton-sensitive ion channel. Our observation that nmrASIC3 forms nonfunctional homomers may reflect a further adaptation of the naked mole-rat to living in an environment with high-carbon dioxide levels.

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“…We also investigated the ability of mASIC3 and nmrASIC3 to form heteromers with rASIC2a and found that as shown previously (7,43) coexpression of mASIC3 and rASIC2a resulted in currents with an I sus /I peak that was significantly greater than that produced by either mASIC3 or rASIC2a homomers (mASIC3+rASIC2a: 141 ± 25, n = 13 vs. mASIC3: 48 ± 4 %, n = 23, p < 0.001 and rASIC2a 29 ± 6 %, n = 8, p < 0.001 Fig. 4A and D).…”

Section: Nmrasic3 Forms Functional Asic Heteromers With Other Asic Susupporting

confidence: 66%

Naked mole-rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers

Schuhmacher

¹

,

Callejo

²

,

Srivats

³

et al. 2017

Preprint

0

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Acid-sensing ion channels (ASICs) form both homotrimeric and heterotrimeric ion channels that are activated by extracellular protons and are involved in a wide range of physiological and pathophysiological processes, including pain and anxiety. ASIC proteins can form both homotrimeric and heterotrimeric ion channels. The ASIC3 subunit has been shown to be of particular importance in the peripheral nervous system with pharmacological and genetic manipulations demonstrating a role in pain. Naked mole-rats, despite having functional ASICs, are insensitive to acid as a noxious stimulus and show diminished avoidance of acidic fumes, ammonia and carbon dioxide. Here we cloned naked mole-rat ASIC3 (nmrASIC3) and used a cell surface biotinylation assay to demonstrate that it traffics to the plasma membrane, but using whole-cell patch-clamp electrophysiology we observed that nmrASIC3 is insensitive to both protons and the non-proton ASIC3 agonist 2-Guanidine-4-methylquinazoline (GMQ). However, in line with previous reports of ASIC3 mRNA expression in dorsal root ganglia (DRG) neurons, we found that the ASIC3 antagonist APETx2 reversibly inhibits ASIC-like currents in naked mole-rat DRG neurons. We further show that like the proton-insensitive ASIC2b and ASIC4, nmrASIC3 forms functional, proton sensitive heteromers with other ASIC subunits. An amino acid alignment of ASIC3s between 9 relevant rodent species and human identified unique sequence differences that might underlie the proton insensitivity of nmrASIC3. However, introducing nmrASIC3 differences into rat ASIC3 (rASIC3) produced only minor differences in channel function, and replacing nmrASIC3 sequence with that of rASIC3 did not produce a proton-sensitive ion channel. Our observation that nmrASIC3 forms nonfunctional homomers may reflect a further adaptation of the naked mole-rat to living in an environment with high-carbon dioxide levels. IntroductionAcid-sensing ion channels (ASICs) are part of the epithelial sodium channel (ENaC)/degenerin (DEG) superfamily of ion channels and are implicated in a diverse range of physiological and pathophysiological processes, ranging from learning and memory to mechanosensation and pain (1). In mammals, there are 4 ASIC encoding genes, which generate 6 distinct ASIC subunits due to splice variants in the ACCN2 and ACCN1 genes producing a and b variants of the ASIC1 and ASIC2 subunits respectively: ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3 and ASIC4. The crystal structure of ASIC1 demonstrated that ASICs form trimeric ion channels (2) and although evidence exists for the formation of ASIC/ENaC heteromers (3, 4), it is largely thought that functional ASICs are the result of either homo-or heterotrimeric arrangement of ASIC subunits.Unlike transient receptor potential vanilloid 1 (TRPV1) that produces a sustained

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“…ASIC3 is mainly located in the peripheral dorsal root ganglion (DRG) neurons [ 4 , 42 ]. Other locations of ASIC3 in the PNS include the spiral ganglia, nodose ganglia, trigeminal ganglia, and neurons in the bladder [ 43 ]. In addition to forming functional channels with other ASIC subunits, such as ASIC1a [ 44 ], ASIC3 is also associated with the P2X3 ion channel [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

Acid-Sensing Ion Channels and Mechanosensation

Ruan

¹

,

Tribble

²

,

Peterson

³

et al. 2021

IJMS

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Acid-sensing ion channels (ASICs) are mainly proton-gated cation channels that are activated by pH drops and nonproton ligands. They are part of the degenerin/epithelial sodium channel superfamily due to their sodium permeability. Predominantly expressed in the central nervous system, ASICs are involved in synaptic plasticity, learning/memory, and fear conditioning. These channels have also been implicated in multiple disease conditions, including ischemic brain injury, multiple sclerosis, Alzheimer’s disease, and drug addiction. Recent research has illustrated the involvement of ASICs in mechanosensation. Mechanosensation is a form of signal transduction in which mechanical forces are converted into neuronal signals. Specific mechanosensitive functions have been elucidated in functional ASIC1a, ASIC1b, ASIC2a, and ASIC3. The implications of mechanosensation in ASICs indicate their subsequent involvement in functions such as maintaining blood pressure, modulating the gastrointestinal function, and bladder micturition, and contributing to nociception. The underlying mechanism of ASIC mechanosensation is the tether-gate model, which uses a gating-spring mechanism to activate ASIC responses. Further understanding of the mechanism of ASICs will help in treatments for ASIC-related pathologies. Along with the well-known chemosensitive functions of ASICs, emerging evidence has revealed that mechanosensitive functions of ASICs are important for maintaining homeostasis and contribute to various disease conditions.

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ASIC2a-dependent increase of ASIC3 surface expression enhances the sustained component of the currents

Cited by 6 publications

References 33 publications

Naked mole-rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers

Naked mole-rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers

Naked mole-rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers

Acid-Sensing Ion Channels and Mechanosensation

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