Relationship between rat retinal degeneration and potassium channel KCNQ5 expression

Caminos, Elena; Vaquero, Cecilia F.; Martinez-Galán, Juan R.

doi:10.1016/j.exer.2014.12.009

Cited by 22 publications

(27 citation statements)

References 46 publications

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“…30 Although most neurons do not contain these particular channels, rod and cone cells have been shown to contain message and protein for K v 7.4 and 7.5. 31,32 The function of these proteins, possibly occurring as channels, in photoreceptors currently is unknown.…”

Section: Discussionmentioning

confidence: 99%

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment

Townes‐Anderson

Wang

Halasz

et al. 2017

Trans. Vis. Sci. Tech.

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PurposeRetinal detachment disrupts the rod-bipolar synapse in the outer plexiform layer by retraction of rod axons. We showed that breakage is due to RhoA activation whereas inhibition of Rho kinase (ROCK), using Y27632, reduces synaptic damage. We test whether the ROCK inhibitor fasudil, used for other clinical applications, can prevent synaptic injury after detachment.MethodsDetachments were made in pigs by subretinal injection of balanced salt solution (BSS) or fasudil (1, 10 mM). In some animals, fasudil was injected intravitreally after BSS-induced detachment. After 2 to 4 hours, retinae were fixed for immunocytochemistry and confocal microscopy. Axon retraction was quantified by imaging synaptic vesicle label in the outer nuclear layer. Apoptosis was analyzed using propidium iodide staining. For biochemical analysis by Western blotting, retinal explants, detached from retinal pigmented epithelium, were cultured for 2 hours.ResultsSubretinal injection of fasudil (10 mM) reduced retraction of rod spherules by 51.3% compared to control detachments (n = 3 pigs, P = 0.002). Intravitreal injection of 10 mM fasudil, a more clinically feasible route of administration, also reduced retraction (28.7%, n = 5, P < 0.05). Controls had no photoreceptor degeneration at 2 hours, but by 4 hours apoptosis was evident. Fasudil 10 mM reduced pyknotic nuclei by 55.7% (n = 4, P < 0.001). Phosphorylation of cofilin and myosin light chain, downstream effectors of ROCK, was decreased with 30 μM fasudil (n = 8–10 explants, P < 0.05).ConclusionsInhibition of ROCK signaling with fasudil reduced photoreceptor degeneration and preserved the rod-bipolar synapse after retinal detachment.Translational RelevanceThese results support the possibility, previously tested with Y27632, that ROCK inhibition may attenuate synaptic damage in iatrogenic detachments.

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Section: Discussionmentioning

confidence: 99%

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment

Townes‐Anderson

Wang

Halasz

et al. 2017

Trans. Vis. Sci. Tech.

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“… 39 Moreover, the reliability of the technique for demonstrating protein interactions was proven in rodent retinal sections. 40–42 For the assay, antibodies against proteins which localize to different mitochondrial compartments were used: five inner membrane proteins: OPA1, SDHA1, ND6, NDUFB6, and NDUFS1 and two outer membrane proteins: VDAC and TOMM20. OPA1 is essential for preserving organelle dynamics 43 and was described as interacting with the 70-kDa (FP) subunit of complex II protein, SDHA1.…”

Section: Resultsmentioning

confidence: 99%

“…The technique has been reported as effective demonstrating protein interactions in rodent retinal sections. 41 , 42 Assays were performed with retinal sections from 4 independent eyes treated with AAV2/2-ND4 (5 × 10 9 VG) obtained 3–6 months postinjection or their fellow untreated eyes. The manufacturer’s instructions were essentially followed using the different antibodies listed in Supplementary Table S2 .…”

Section: Methodsmentioning

confidence: 99%

Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss

Cwerman-Thibault

Augustin

Lechauve

et al. 2015

Molecular Therapy - Methods & Clinical Development

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Leber hereditary optic neuropathy is due to mitochondrial DNA mutations; in ~70% of all cases, a point mutation in the mitochondrial NADH dehydrogenase subunit 4, ND4, gene leads to central vision loss. We optimized allotopic expression (nuclear transcription of a gene that is normally transcribed inside the mitochondria) aimed at designing a gene therapy for ND4; its coding sequence was associated with the cis-acting elements of the human COX10 mRNA to allow the efficient mitochondrial delivery of the protein. After ocular administration to adult rats of a recombinant adeno-associated viral vector containing the human ND4 gene, we demonstrated that: (i) the sustained expression of human ND4 did not lead to harmful effects, instead the human protein is efficiently imported inside the mitochondria and assembled in respiratory chain complex I; (ii) the presence of the human protein in the experimental model of Leber hereditary optic neuropathy significantly prevents retinal ganglion cell degeneration and preserves both complex I function in optic nerves and visual function. Hence, the use of optimized allotopic expression is relevant for treating mitochondrial disorders due to mutations in the organelle genome.

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“…Besides the lack of KCNQ4 mRNA, KCNQ5 mRNA was completely missing and a reduction of KCNQ2 together with a relative increase in KCNQ3 was seen. Alterations in the expression pattern of KCNQ channel subunits were observed in different tissues during pathologies such as hypertension, vascular tumors or retinal degeneration, which in turn contributes to alterations in cellular properties (Jepps et al, 2011;Caminos et al, 2015;Serrano-Novillo et al, 2020). In conclusion, these observations rise the possibility that KCNQ4 is not only important as one of the subunits forming channels for M-current, but might be a potential regulator of the expression of other Mcurrent subunits, setting its physiological function.…”

Section: Discussionmentioning

confidence: 99%

The KCNQ4-mediated M-current regulates the circadian rhythm in mesopontine cholinergic neurons

Tsogbadrakh

Stupniki

Kovács

et al. 2020

Preprint

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The M-current is a voltage gated potassium current inhibited by muscarinic activation and affected by several other G-protein coupled receptors. Its channels are formed by KCNQ subunits, from which KCNQ4 is restricted to certain brainstem structures. We sought evidence for the function of the M-current in the pedunculopontine nucleus (PPN) and the contribution of KCNQ4 subunits to the M-current and aimed to find its functional significance in the PPN. We found that cholinergic inputs of the PPN can effectively inhibit M-current. This current is capable of synchronizing neighboring neurons and inhibition of the M-current decreases neuronal synchronization. We showed that only a subpopulation of cholinergic neurons has KCNQ4-dependent M-current. The KCNQ4 subunit expression potentially regulates the presence of other KCNQ subunits. Deletion of KCNQ4 leads to alterations in adaptation of activity to light-darkness cycles, thus representing the potential role of KCNQ4 in regulation of sleep-wakefulness cycles. The presence of this protein restricted to certain brainstem nuclei raises the possibility that it might be a potential target for selective therapeutic interventions affecting the reticular activating system.

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Relationship between rat retinal degeneration and potassium channel KCNQ5 expression

Cited by 22 publications

References 46 publications

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment

Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss

The KCNQ4-mediated M-current regulates the circadian rhythm in mesopontine cholinergic neurons

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