Acid-sensing ion channels (ASICs) are differentially modulated by anions dependent on their subunit composition

Kusama, Nobuyoshi; Gautam, Mamta; Harding, Anne Marie S.; Snyder, Peter M.; Benson, Christopher J.

doi:10.1152/ajpcell.00216.2012

Cited by 21 publications

(29 citation statements)

References 35 publications

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“…As described previously by Kusama et al (37,38), MeSO 3 Ϫ and I Ϫ accelerated the desensitization of ASIC1a (Fig. 3A, left panel).…”

Section: Asic2a-t1asupporting

confidence: 84%

“…1B). Remarkably, ASIC2a anion modulation is only partially dependent on the Cl Ϫ binding site at the thumb and ␤-ball domains (37). Our studies indicate that transposition of the thumb domain of ASIC1a into ASIC2a is sufficient to change its anion selectivity.…”

Section: Discussionmentioning

confidence: 68%

“…Together, these results suggest that the thumb domain has an important role in ASIC desensitization. ASIC activity is modulated by extracellular anions (37,38). Remarkably, the solved structure of ASIC1a in the desensitized state revealed the presence of a Cl Ϫ binding site formed by two residues (Arg 309 and Glu 313 ) of the ␣4 helix of one subunit and a residue (Lys 211 ) in the ␤-ball of the neighboring subunit (30).…”

Section: Resultsmentioning

confidence: 99%

“…ASIC2a desensitization is only partially dependent on the intersubunit Cl Ϫ binding site (37). To determine whether acceleration of desensitization by thumb transposing is due to disruption of the Cl Ϫ binding site, we examined the effect of anion substitution on the response to extracellular acidification of ASIC1a, ASIC2a, and chimeras.…”

Section: Resultsmentioning

confidence: 99%

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The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization

Krauson

Carattino

2016

Journal of Biological Chemistry

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Acid-sensing ion channels (ASICs) are cation-selective proton-gated channels expressed in neurons that participate in diverse physiological processes, including nociception, synaptic plasticity, learning, and memory. ASIC subunits contain intracellular N and C termini, two transmembrane domains that constitute the pore, and a large extracellular loop with defined domains termed the finger, ␤-ball, thumb, palm, and knuckle. Here we examined the contribution of the finger, ␤-ball, and thumb domains to activation and desensitization through the analysis of chimeras and the assessment of the effect of covalent modification of introduced Cys at the domain-domain interfaces. Our studies with ASIC1a-ASIC2a chimeras showed that swapping the thumb domain between subunits results in faster channel desensitization. Likewise, the covalent modification of Cys residues at selected positions in the ␤-ball-thumb interface accelerates the desensitization of the mutant channels. Studies of accessibility with thiol-reactive reagents revealed that the ␤-ball and thumb domains reside apart in the resting state but that they become closer to each other in response to extracellular acidification. We propose that the thumb domain moves upon continuous exposure to an acidic extracellular milieu, assisting with the closing of the pore during channel desensitization.Acid-sensing ion channels (ASICs) 2 are voltage-insensitive cation-permeable channels expressed in neurons of the peripheral and central nervous systems that respond to sudden changes in extracellular pH. Four genes that encode for six ASIC subunits and splice variants have been identified in mammals (ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4) (1-10). In the central nervous system, disruption of ASIC1a expression causes a number of learning and memory-related phenotypes (11)(12)(13)(14). Conversely, activation of ASIC1a has been linked to neurotoxicity in a mouse model of brain ischemia (15) and in neurodegenerative diseases such as multiple sclerosis (16), Huntington disease (17), Parkinson disease (18), and spinal cord injury (19). There is a substantial body of research that indicates that ASIC subunits participate in nociception in peripheral neurons (20 -22) as well as in pain processing in the central nervous system (23-25). Therefore, ASICs represent novel therapeutic targets to treat pain as well as neurological diseases.ASIC subunits assemble to form homo-and heterotrimers that display distinct proton sensitivities for activation and desensitization kinetics (26 -29). Although the molecular determinants for channel activation have been extensively investigated, less is known about the mechanisms that promote channel desensitization in the continual presence of protons. ASIC subunits contain two membrane-spanning helices that form the pore of the channel and connect to cytoplasmic N-and C-terminal regions and to a large extracellular loop with defined domains termed the wrist, thumb, finger, ␤-ball, knuckle, and palm (see Fig. 1) (30). In the solved structure o...

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“…As described previously by Kusama et al (37,38), MeSO 3 Ϫ and I Ϫ accelerated the desensitization of ASIC1a (Fig. 3A, left panel).…”

Section: Asic2a-t1asupporting

confidence: 84%

Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization

Krauson

Carattino

2016

Journal of Biological Chemistry

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“…Targeted disruption of ASIC subunits in vivo [9, 26, 39, 43, 84] has allowed for the observation of changes in acid-evoked currents in various CNS/PNS neurons and the impact on the pathological outcomes yielding insight to the functions of the specific subunit. In a mouse model of multiple sclerosis, Friese and colleagues observed a decrease in clinical deficit in ASIC1a −/− mice associated with reduced axonal degeneration in comparison with WT mice [26].…”

Section: Asic Regulationmentioning

confidence: 99%

Translational Strategies for Neuroprotection in Ischemic Stroke—Focusing on Acid-Sensing Ion Channel 1a

O’Bryant

Vann

Xiong

2014

Transl. Stroke Res.

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Ischemic stroke contributes to the majority of brain injuries and remains to be a leading cause of death and long-term disability. Despite the devastating pathology and high incidence of disease, there remain only few treatment options (tPA and endovascular procedures), which may be hampered by time dependent administration among a variety of other factors. Promising research of glutamate receptor antagonists has been unsuccessful in clinical trial. But, the mechanism by which glutamate receptors initiate injury by excessive calcium overload has spurred investigation of new and potentially successful candidates for stroke therapy. Acid sensing ion channels (ASICs) may contribute to poor stroke prognosis due to localized drop in brain pH, resulting in excessive calcium overload, independent of glutamate activation. Accumulating studies targeting ASICs have underscored the importance of understanding inhibition, regulation, desensitization and trafficking of this channel and its role in disease. This review will discuss potential directions in translational ASIC research for future stroke therapies.

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Photomodulation of the ASIC1a acidic pocket destabilizes the open state

Rook,

McCullock,

Couch

et al. 2023

Protein Science

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Acid‐sensing ion channels (ASICs) are important players in detecting extracellular acidification throughout the brain and body. ASICs have large extracellular domains containing two regions replete with acidic residues: the acidic pocket and the palm domain. In the resting state, the acidic pocket is in an expanded conformation but collapses in low pH conditions as the acidic side chains are neutralized. Thus, extracellular acidification has been hypothesized to collapse the acidic pocket that, in turn, ultimately drives channel activation. However, several observations run counter to this idea. To explore how collapse or mobility of the acidic pocket is linked to channel gating, we employed two distinct tools. First, we incorporated the photocrosslinkable non‐canonical amino acids (ncAAs) AzF or BzF into several positions in the acidic pocket. At both E315 and Y318, AzF incorporation followed by UV irradiation led to right shifts in pH response curves and accelerations of desensitization and deactivation, consistent with restrictions of acidic pocket mobility destabilizing the open state. Second, we reasoned that because Cl‐ ions are found in the open and desensitized structures but absent in the resting state structures, Cl‐ substitution would provide insight into how stability of the pocket is linked to gating. Anion substitution resulted in faster deactivation and desensitization, consistent with the acidic pocket regulating the stability of the open state. Taken together, our data support a model where acidic pocket collapse is not essential for channel activation. Rather, collapse of the acidic pocket influences the stability of the open state of the pore.This article is protected by copyright. All rights reserved.

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Acid-sensing ion channels (ASICs) are differentially modulated by anions dependent on their subunit composition

Cited by 21 publications

References 35 publications

The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization

The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization

Translational Strategies for Neuroprotection in Ischemic Stroke—Focusing on Acid-Sensing Ion Channel 1a

Photomodulation of the ASIC1a acidic pocket destabilizes the open state

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