A Novel Subtype of Astrocytes Expressing TRPV4 (Transient Receptor Potential Vanilloid 4) Regulates Neuronal Excitability via Release of Gliotransmitters
Open accessAbstract
Astrocytes play active roles in the regulation of synaptic transmission. Neuronal excitation can evoke Ca(2+) transients in astrocytes, and these Ca(2+) transients can modulate neuronal excitability. Although only a subset of astrocytes appears to communicate with neurons, the types of astrocytes that can regulate neuronal excitability are poorly characterized. We found that ∼30% of astrocytes in the brain express transient receptor potential vanilloid 4 (TRPV4), indicating that astrocytic subtypes can be classified on the basis of their expression patterns. When TRPV4(+) astrocytes are activated by ligands such as arachidonic acid, the activation propagates to neighboring astrocytes through gap junctions and by ATP release from the TRPV4(+) astrocytes. After activation, both TRPV4(+) and TRPV4(-) astrocytes release glutamate, which acts as an excitatory gliotransmitter to increase synaptic transmission through type 1 metabotropic glutamate receptor (mGluR). Our results indicate that TRPV4(+) astrocytes constitute a novel subtype of the population and are solely responsible for initiating excitatory gliotransmitter release to enhance synaptic transmission. We propose that TRPV4(+) astrocytes form a core of excitatory glial assembly in the brain and function to efficiently increase neuronal excitation in response to endogenous TRPV4 ligands.
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Activation of TRPV4 in astrocytes promotes ATP and glutamate release, which induces reactive astrocyte.
“Activation of TRPV4 in astrocytes has been reported to promote ATP and glutamate release, which induces reactive astrocyte (Shibasaki et al. 2014).”
From Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte (2024) · cites this paper as Shibasaki et al. 2014
The Results and Discussion report that TRPV4 activation promotes ATP and glutamate release from astrocytes. The Discussion describes excitation of neighboring astrocytes and enhanced synaptic activity, but does not establish that this release induces reactive astrocytes. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAstrocytes expressing TRPV4 are approximately 30% of total astrocytes.
“Although astrocytes expressing TRPV4 are only approximately 30% of total astrocytes, the increase in intracellular Ca2+ due to TRPV4 activation is thought to be propagated to adjacent astrocytes through gap junctions (Shibasaki et al. 2014).”
From Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte (2024) · cites this paper as Shibasaki et al. 2014
Activation of TRPV4-positive astrocytes leads to the release of ATP, further inducing the activation of TRPV4-negative astrocytes.
“Furthermore, the activation of TRPV4-positive astrocytes leads to the release of ATP, further inducing the activation of TRPV4-negative astrocytes (Shibasaki et al. 2014).”
From Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte (2024) · cites this paper as Shibasaki et al. 2014
The increase in intracellular Ca2+ due to TRPV4 activation is propagated to adjacent astrocytes through gap junctions.
“Although astrocytes expressing TRPV4 are only approximately 30% of total astrocytes, the increase in intracellular Ca2+ due to TRPV4 activation is thought to be propagated to adjacent astrocytes through gap junctions (Shibasaki et al. 2014).”
From Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte (2024) · cites this paper as Shibasaki et al. 2014
A specific population of astrocytes functionally express TRPV4.
“Since a specific population of astrocytes functionally express TRPV4 (Shibasaki et al. 2014)”
From Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte (2024) · cites this paper as Shibasaki et al. 2014
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Research works printed but not linked: 7
- Kettenmann H, R. B., eds. (2005) Neuroglia, pp. 135-148, Oxford Univer- sity Press, New York
- Pannasch, U., Vargová, L., Reingruber, J., Ezan, P., Holcman, D., Giaume, C., Syková, E., and Rouach, N. (2011) Astroglial networks scale synaptic activity and plasticity. Proc. Natl. Acad. Sci. U.S.A. 108, 8467-8472
- Sasaki, T., Beppu, K., Tanaka, K. F., Fukazawa, Y., Shigemoto, R., and Matsui, K. (2012) Application of an optogenetic byway for perturbing neuronal activity via glial photostimulation. Proc. Natl. Acad. Sci. U.S.A. 109, 20720 -20725
- Benfenati, V., Caprini, M., Dovizio, M., Mylonakou, M. N., Ferroni, S., Ottersen, O. P., and Amiry-Moghaddam, M. (2011) An aquaporin-4/tran- sient receptor potential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes. Proc. Natl. Acad. Sci. U.S.A. 108, 2563-2568
- Koizumi, S., Fujishita, K., Tsuda, M., Shigemoto-Mogami, Y., and Inoue, K. (2003) Dynamic inhibition of excitatory synaptic transmission by as- trocyte-derived ATP in hippocampal cultures. Proc. Natl. Acad. Sci. U.S.A. 100, 11023-11028
- Dunn, K. M., Hill-Eubanks, D. C., Liedtke, W. B., and Nelson, M. T. (2013) TRPV4 channels stimulate Ca 2ϩ -induced Ca 2ϩ release in astrocytic end- feet and amplify neurovascular coupling responses. Proc. Natl. Acad. Sci.
- Takayama, Y., Shibasaki, K., Suzuki, Y., Yamanaka, A., and Tominaga, M. (2014) Modulation of water efflux through functional interaction between TRPV4 and TMEM16A/anoctamin 1. FASEB J., in press
Cited by
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Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte
Muhamad, N. A., Masutani, K., Furukawa, S., Yuri, S., Toriyama, M., Matsumoto, C., Itoh, S., Shinagawa, Y., Isotani, A., Toriyama, M., et al. (2024) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-024-01482-5 · Cited by 8 · see citing works
- Authors
- Shibasaki, K., Ikenaka, K., Tamalu, F., Tominaga, M., & Ishizaki, Y.
- Affiliations
- Gunma University (JP)
- The Graduate University for Advanced Studies, SOKENDAI (JP)
- Saitama Medical University (JP)
- National Institutes of Natural Sciences (JP)
- Corresponding author
- Shibasaki, Koji
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 289
- Issue
- 21
- Pages
- 14470-14480
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4031503
- OpenAlex
- W2056400855
- Cited by
- 118
- References
- 0
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 14 · 2023: 10 · 2022: 10 · 2021: 5 · 2020: 16 · 2019: 7 · 2018: 18 · 2017: 3 · 2016: 10 · 2015: 6 · 2014: 3
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- TRPV4, astrocytes, astrocyte subtypes, gliotransmitters, glutamate release, neuronal excitability, synaptic transmission, electrical coupling, ATP release, arachidonic acid, calcium transients
- MeSH terms
- Adenosine Triphosphate, Animals, Astrocytes, Calcium, Cells, Cultured, Humans, Immunohistochemistry, Mice, Inbred C57BL, Synaptic Transmission, Neuroglia, Neurons, Phorbols, Gene Expression, Arachidonic Acid, In Situ Hybridization, Receptors, Metabotropic Glutamate, Mice, Knockout, Patch-Clamp Techniques, Glutamic Acid, Excitatory Postsynaptic Potentials, Calcium Signaling, TRPV Cation Channels, Mice, HEK293 Cells
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