TRPA1 Channels Mediate Human Gingival Fibroblast Response to Phenytoin
Abstract
Drug-induced gingival enlargement (GE) is a frequent adverse effect observed in patients treated with anticonvulsant, immunosuppressant, and some antihypertensive medications-the antiepileptic phenytoin being the main drug associated with GE due to its high incidence (around 50%). The molecular mechanisms behind drug-induced gingival overgrowth are still unknown. By reverse transcription polymerase chain reaction, we demonstrate that the calcium-permeable ion channels TRPA1, TRPV1, and its capsaicin-insensitive isoform TRPV1b are expressed in human gingival fibroblasts (HGFs), the most abundant cellular type in periodontal tissue. Cultured HGFs responded with intracellular calcium elevations to phenytoin and to the canonical TRPA1 agonist allyl isothiocyanate. Application of phenytoin activated a nonselective cationic current in HGFs with a typical signature for TRPA1 channels. Moreover, this activation was blocked by HC030031, a specific TRPA1 blocker. Similarly, the use of shRNAs against hTRPA1 in HGFs reduced TRPA1 expression and activation by phenytoin. In addition, we show that phenytoin increased intracellular calcium levels in cells transfected with mouse or human TRPA1 channels. Responses to phenytoin were not observed in untransfected cells or cells expressing TRPM8 or TRPV1. The activation of HGFs by phenytoin was markedly reduced in the presence of antioxidant vitamins: ascorbic acid, folic acid, and α-tocopherol. By performing cell proliferation assays, we found t…
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FOXO-1 enhances production of TGF-β contributing to gingival overgrowth.
“FOXO-1 enhances the production of TGF-β contributing to gingival overgrowth.”
From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [72]
TRPA1, TRPV1 and TRPV1b are expressed in human gingival fibroblasts, in which phenytoin increases intracellular calcium levels by acting on these ion channels.
“The calcium-permeable ion channels TRPA1 [74], Transient receptor potential channels, of the vanilloid subtype (TRPV1), and its capsaicin-insensitive isoform TRPV1b are expressed in Human Gingival Fibroblasts (HGFs), in which phenytoin increase the intracellular calcium levels by acting on the mentioned ion channels [ 72].”
From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [72]
Phenytoin does not augment the proliferative rate of HGFs whereas it induces extracellular matrix accumulation of collagen.
“Further, phenytoin did not augment the proliferative rate of HGFs whereas it induced extracellular matrix accumulation of collagen [72].”
From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [72]
Phenytoin inhibits FOXO-1.
“Phenytoin is known to inhibit FOXO-1 [72, 73].”
From An Update on the Mechanisms of Phenytoin Induced Gingival Overgrowth (2019) · cites this paper as [72]
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- Authors
- López-González, M. J., Luis, E., Fajardo, O., Meseguer, V., Gers-Barlag, K., Niñerola, S., & Viana, F.
- Affiliations
- Instituto de Neurociencias de Alicante, Universidad Miguel Hernández–CSIC, Alicante, Spain
- Instituto de Neurociencias (ES)
- Corresponding author
- Viana, F.
- Venue
- Journal of Dental Research
- Publisher
- SAGE Publications
- Published
- 2017-03-06
- Volume
- 96
- Issue
- 7
- Pages
- 832-839
- ISSN
- 0022-0345 (ISSN-L)
- 1544-0591
- OpenAlex
- W2592767669
- Cited by
- 20
- References
- 39
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 2
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Dental Research (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Spanish MINECO (SAF2013-45608-R, SEV- 2013-0317)
- Topics
- Health Sciences › Health Professions › Pharmacy › Oral and gingival health research
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Keywords
- TRPA1 channel, phenytoin, drug-induced gingival hyperplasia, gingival fibroblasts, intracellular calcium signaling, TRPV1, allyl isothiocyanate, HC-030031, antioxidant vitamins, extracellular matrix accumulation, collagen deposition, anticonvulsant adverse effects
- MeSH terms
- TRPA1 Cation Channel, Acetanilides, Animals, Anticonvulsants, Antioxidants, Cell Line, Fibroblasts, Gingiva, Humans, Nerve Tissue Proteins, Phenytoin, Purines, Staining and Labeling, Blotting, Western, Calcium Channels, Patch-Clamp Techniques, Gingival Overgrowth, Transient Receptor Potential Channels, TRPV Cation Channels, Real-Time Polymerase Chain Reaction
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