Journal article
Acid Sensing Ion Channel 1a (ASIC1a) Mediates Activity-induced Pain by Modulation of Heteromeric ASIC Channel Kinetics
Neuroscience, Vol.386, pp.166-174
08/21/2018
DOI: 10.1016/j.neuroscience.2018.06.033
PMID: 29964154
Abstract
•Activity-induced hyperalgesia is prevented by blockade of ASIC1a with psalmotoxin, but not by genetic deletion of ASIC1a.•Psalmotoxin alters kinetics of heteromeric ASICs.•In ASIC1a/2/3 heteromers psalmotoxin alters desensitization kinetics, but not the amplitude of pH-evoked currents.•In ASIC1a/3 heteromers, psalmotoxin decreased pH-evoked currents and potentiated steady-state desensitization.
Chronic muscle pain is acutely worsened by exercise. Acid sensing ion channels (ASIC) are heteromeric channels expressed in muscle sensory neurons that detect decreases in pH. We have previously shown ASIC3 is important in activity-induced hyperalgesia. However, ASICs form heteromers with ASIC1a being a key component in sensory neurons. Therefore, we studied the role of ASIC1a in mice using behavioral pharmacology and genetic deletion in a model of activity-induced hyperalgesia. We found ASIC1a−/− mice developed mechanical hyperalgesia similar to wild-type mice, but antagonism of ASIC1a, with psalmotoxin, prevented development of mechanical hyperalgesia in wild-type mice, but not in ASIC1a−/− mice. To explain this discrepancy, we then performed electrophysiology studies of ASICs and examined the effects of psalmotoxin on ASIC heteromers. We expressed ASIC1a, 2 and 3 heteromers or ASIC1 and 3 heteromers in CHO cells, and examined the effects of psalmotoxin on pH sensitivity. Psalmotoxin significantly altered the properties of ASIC hetomeric channels. Specifically, in ASIC1a/2/3 heteromers, psalmotoxin slowed the kinetics of desensitization, slowed the recovery from desensitization, and inhibited pH-dependent steady-state desensitization, but had no effect on pH-evoked current amplitudes. We found a different pattern in ASIC1a/3 heteromers. There was a significant leftward shift in the pH dose response of steady-state desensitization and decrease in pH-evoked current amplitudes. These results suggest that blockade of ASIC1a modulates the kinetics of heteromeric ASICs to prevent development of activity-induced hyperalgesia. These data suggest ASIC1a is a key subunit in heteromeric ASICs and may be a pharmacological target for treatment of musculoskeletal pain.
Details
- Title: Subtitle
- Acid Sensing Ion Channel 1a (ASIC1a) Mediates Activity-induced Pain by Modulation of Heteromeric ASIC Channel Kinetics
- Creators
- Nicholas S Gregory - Department of Physical Therapy and Rehabilitation Science, The University of Iowa, Iowa City, IA 52242, United StatesMamta Gautam - Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242, United StatesChristopher J Benson - Department of Neuroscience, The University of Iowa, Iowa City, IA 52242, United StatesKathleen A Sluka - Department of Physical Therapy and Rehabilitation Science, The University of Iowa, Iowa City, IA 52242, United States
- Resource Type
- Journal article
- Publication Details
- Neuroscience, Vol.386, pp.166-174
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/j.neuroscience.2018.06.033
- PMID
- 29964154
- ISSN
- 0306-4522
- eISSN
- 1873-7544
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: AR053509, AR052316, AR061371
- Language
- English
- Date published
- 08/21/2018
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Nursing; Physical Therapy and Rehabilitation Science; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040293502771
Metrics
40 Record Views