Polymodal TRPV1 and TRPV4 Sensors Colocalize but Do Not Functionally Interact in a Subpopulation of Mouse Retinal Ganglion Cells

Lakk, Mónika; Young, Derek; Baumann, Jackson M.; Jo, Andrew; Hu, Hongzhen; Križaj, David

doi:10.3389/fncel.2018.00353

Cited by 40 publications

(37 citation statements)

References 84 publications

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“…TRPV1 channels densely accumulate in nociceptor cells of dorsal root ganglia to transduce noxious sensory input into the electrochemical responses of the spinal nerve (Simone et al, 1989;Caterina et al, 1997Caterina et al, , 2000Bolcskei et al, 2005). Recent evidence shows widespread TRPV1 expression in the central nervous system (CNS) tissues, including the cortex, hippocampus, hypothalamus, and retina (Mezey et al, 2000;Roberts et al, 2004;Cristino et al, 2006;Sappington et al, 2009Sappington et al, , 2015Jo et al, 2017;Lakk et al, 2018). TRPV1 has also been implicated in neurodegenerative disorders such as Alzheimer's disease (Jayant et al, 2016;Balleza-Tapia et al, 2018), Parkinson's disease (Marinelli et al, 2003;Morgese et al, 2007;Nam et al, 2015;Chung et al, 2017), Huntington's disease (Lastres-Becker et al, 2003), and glaucomatous optic neuropathy, or glaucoma (Ward et al, 2014;Weitlauf et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Glaucoma is the leading cause of irreversible blindness (Quigley and Broman, 2006), involving sensitivity to intraocular pressure (IOP) that stresses retinal ganglion cell (RGC) axons as they form the optic nerve (Calkins, 2012). Many RGCs express TRPV1 channels (Jo et al, 2017;Lakk et al, 2018), localizing to dendrites, unmyelinated axon segment, and cell body, where it increases with short-term elevations in IOP (Sappington et al, 2009(Sappington et al, , 2015Weitlauf et al, 2014) but is negligible within the optic nerve itself (Choi et al, 2015). Even so, Trpv1 −/− accelerates optic nerve degeneration with elevated IOP and increases the depolarization necessary for RGCs to produce action potentials (Ward et al, 2014;Weitlauf et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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TRPV1 Tunes Optic Nerve Axon Excitability in Glaucoma

et al. 2020

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The transient receptor potential vanilloid member 1 (TRPV1) in the central nervous system may contribute to homeostatic plasticity by regulating intracellular Ca 2+ , which becomes unbalanced in age-related neurodegenerative diseases, including Alzheimer's and Huntington's. Glaucomatous optic neuropathy-the world's leading cause of irreversible blindness-involves progressive degeneration of retinal ganglion cell (RGC) axons in the optic nerve through sensitivity to stress related to intraocular pressure (IOP). In models of glaucoma, genetic deletion of TRPV1 (Trpv1 −/−) accelerates RGC axonopathy in the optic projection, whereas TRPV1 activation modulates RGC membrane polarization. In continuation of these studies, here, we found that Trpv1 −/− increases the compound action potential (CAP) of optic nerves subjected to short-term elevations in IOP. This IOP-induced increase in CAP was not directly due to TRPV1 channels in the optic nerve, because the TRPV1-selective antagonist iodoresiniferatoxin had no effect on the CAP for wild-type optic nerve. Rather, the enhanced CAP in Trpv1 −/− optic nerve was associated with increased expression of the voltagegated sodium channel subunit 1.6 (NaV1.6) in longer nodes of Ranvier within RGC axons, rendering Trpv1 −/− optic nerve relatively insensitive to NaV1.6 antagonism via 4,9-anhydrotetrodotoxin. These results indicate that with short-term elevations in IOP, Trpv1 −/− increases axon excitability through greater NaV1.6 localization within longer nodes. In neurodegenerative disease, native TRPV1 may tune NaV expression in neurons under stress to match excitability to available metabolic resources.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TRPV1 Tunes Optic Nerve Axon Excitability in Glaucoma

et al. 2020

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“…The immunostaining protocols were as described previously. 33,34 Briefly, corneas were dissected along the sclero-corneal rim and fixed for 20 minutes in 4% ; mouse anti-Pannexin1, 1:100, Santa Cruz Biotech) were diluted (PBS with 2% BSA and 0.2% Triton X-100) and applied overnight at 4 0 C, followed by 1 hour incubation in fluorophoreconjugated goat anti-rabbit and mouse AlexaFluor 488 and/or 594 secondary antibodies (1:500, Life Technologies) at room temperature. The sections were mounted with DAPI-Fluoromount-G (Southern Biotech (Birmingham, AL, USA)).…”

Section: Immunocytochemistrymentioning

confidence: 99%

“…12 Given the unreliability of TRPV1 antibodies, 31 we evaluated TRPV1 expression in TRPV1Cre:Ai9 corneas in which TRPV1 expression manifests as tdTomato fluorescence. 34,43 Figure 1E shows that the majority of CECs lacks tdT expression. Indicating low Trpv1 mRNA expression in the mouse CE ( Fig.…”

Section: Trpv4 the Dominant Thermotrp Isoform In Cecs Is Distributementioning

confidence: 99%

Polymodal Sensory Transduction in Mouse Corneal Epithelial Cells

Lapajne

Lakk

Yarishkin

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Contact lenses, osmotic stressors, and chemical burns may trigger severe discomfort and vision loss by damaging the cornea, but the signaling mechanisms used by corneal epithelial cells (CECs) to sense extrinsic stressors are not well understood. We therefore investigated the mechanisms of swelling, temperature, strain, and chemical transduction in mouse CECs. METHODS. Intracellular calcium imaging in conjunction with electrophysiology, pharmacology, transcript analysis, immunohistochemistry, and bioluminescence assays of adenosine triphosphate (ATP) release were used to track mechanotransduction in dissociated CECs and epithelial sheets isolated from the mouse cornea. RESULTS. The transient receptor potential vanilloid (TRPV) transcriptome in the mouse corneal epithelium is dominated by Trpv4, followed by Trpv2, Trpv3, and low levels of Trpv1 mRNAs. TRPV4 protein was localized to basal and intermediate epithelial strata, keratocytes, and the endothelium in contrast to the cognate TRPV1, which was confined to intraepithelial afferents and a sparse subset of CECs. The TRPV4 agonist GSK1016790A induced cation influx and calcium elevations, which were abolished by the selective blocker HC067047. Hypotonic solutions, membrane strain, and moderate heat elevated [Ca 2+ ] CEC with swelling-and temperature-, but not strain-evoked signals, sensitive to HC067047. GSK1016790A and swelling evoked calcium-dependent ATP release, which was suppressed by HC067027 and the hemichannel blocker probenecid. CONCLUSIONS. These results demonstrate that cation influx via TRPV4 transduces osmotic and thermal but not strain inputs to CECs and promotes hemichannel-dependent ATP release. The TRPV4-hemichannel-ATP signaling axis might modulate corneal pain induced by excessive mechanical, osmotic, and chemical stimulation.

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“…Die Zellkörper der RGZs exprimieren an ihrer äußeren Zellmembran sogenannte mechanosensitive Proteine, z. B. den Ionenkanal TRPV4 [13]. Dieser reagiert auf Druckveränderungen mit seiner Öffnung, was zum Einstrom von schädlichen Kationen in die Zelle führt.…”

Section: äTiologie Der Erkrankungunclassified

Aktuelle Forschungsbemühungen zur Neuroprotektion, Verlauf und Behandlung eines Glaukoms

Jacobi

Zyl

2020

Klin Monatsbl Augenheilkd

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ZusammenfassungDas Glaukom ist eine neurodegenerative Erkrankung, die mit der Zeit zu irreversibler Erblindung führt. Als bestimmendes Merkmal hier gilt der Verlust von retinalen Ganglienzellen (RGZ) im Auge und ihrer Axone im Sehnerv. Ein erhöhter Augeninnendruck (intraokularer Druck, IOD) gilt als Hauptrisikofaktor für die Entstehung eines Glaukoms, jedoch zeigt sich, dass dieser weder notwendig noch ausreichend für die Entstehung und das Fortschreiten der Erkrankung ist. Dies hat die Forschung und Entwicklung neuer Strategien zur Erkennung und Behandlung von Glaukomen mit dem Schwerpunkt auf Neuroprotektion – dem Schutz von RGZs vor dem Sterben – motiviert. Zusätzlich ist es im Bereich der Diagnose und Behandlung durch eine Reduktion des IOD in den letzten Jahren zur Entwicklung neuer Herangehensweisen gekommen. Dieser Artikel gibt einen Überblick über die zurzeit gängigen Theorien der pathophysiologischen Mechanismen, die einer Entstehung eines Glaukoms zugrunde liegen, sowie neuester Forschungsbemühungen mit Fokus auf Neuroprotektion und aktueller präklinischer und klinischer Studien, um eine Diagnose und Therapie des Glaukoms zu verbessern.

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Polymodal TRPV1 and TRPV4 Sensors Colocalize but Do Not Functionally Interact in a Subpopulation of Mouse Retinal Ganglion Cells

Cited by 40 publications

References 84 publications

TRPV1 Tunes Optic Nerve Axon Excitability in Glaucoma

TRPV1 Tunes Optic Nerve Axon Excitability in Glaucoma

Polymodal Sensory Transduction in Mouse Corneal Epithelial Cells

Aktuelle Forschungsbemühungen zur Neuroprotektion, Verlauf und Behandlung eines Glaukoms

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