Oxytocin Expression and Function in the Posterior Retina: A Novel Signaling Pathway

Halbach, Patrick; Pillers, De-Ann M.; York, Nathaniel W.; Asuma, Matti P.; Chiu, Michelle; Luo, Wenxiang; Tokarz, Sara; Bird, Ian M.; Pattnaik, Bikash R.

doi:10.1167/iovs.14-15646

Cited by 24 publications

(28 citation statements)

References 29 publications

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“…We have shown previously that the OXT-induced increase in hfRPE [Ca 2+ ] i was reduced by 87% in the presence of 500 nM of the OXTR-specific antagonist, L-371,257, providing strong evidence that the OXT-induced increase in hfRPE [Ca 2+ ] i was mediated through the OXTR, even when a supraphysiologic dose (6μM) was used. 10 The other specific OXTR antagonist, OTA, in this paper also significantly (> 85 %) reduced the Ca 2+ response to OXT (10 μM), further supporting the explicit activation of OXTR in the RPE. Based on these finding, we used 10μM OXT to ensure maximal activation of cells during perfusion experiments.…”

Section: Discussionsupporting

confidence: 68%

“…10 In the present study, we show that OXT increases hfRPE [Ca 2+ ] i through a GPCR-mediated mechanism whereby the OXT binding to OXTR causes downstream activation of PLC and PIP 2 hydrolysis. In addition, we have shown that heterologously expressed Kir7.1 channels in HEK-OXTR cells, as well as endogenous mouse RPE cell Kir7.1 channels are subject to OXTR inhibition.…”

Section: Discussionsupporting

confidence: 55%

“…10 hfRPE cells were stimulated by OXT concentrations ranging from 0.01 to 100 μM, and [Ca 2+ ] i represented by R (340/380), was measured. OXT concentrations of 0.01, 1, and 100 μM showed a progressive increase in [Ca 2+ ] i (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…10 Moreover, the oxytocin receptor (OXTR) is expressed in the retinal pigment epithelium (RPE) where we have shown that OXT can induce an increase in [Ca 2+ ] i , leading to our hypothesis that oxytocinergic signaling may serve as a means for communication between cone photoreceptors and the RPE. 10 OXTR is a GPCR and like the aforementioned receptors, it activates a phospholipase C (PLC)-mediated signaling pathway, thereby stimulating PIP 2 hydrolysis and resulting in a rise in [Ca 2+ ] i . 12 …”

Section: Introductionmentioning

confidence: 99%

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Oxytocin (OXT)-stimulated inhibition of Kir7.1 activity is through PIP 2 -dependent Ca 2+ response of the oxytocin receptor in the retinal pigment epithelium in vitro

York

Halbach

Chiu

et al. 2017

Cellular Signalling

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Oxytocin (OXT) is a neuropeptide that activates the oxytocin receptor (OXTR), a rhodopsin family G-protein coupled receptor. Our localization of OXTR to the retinal pigment epithelium (RPE), in close proximity to OXT in the adjacent photoreceptor neurons, leads us to propose that OXT plays an important role in RPE-retinal communication. An increase of RPE [Ca2+]i in response to OXT stimulation implies that the RPE may utilize oxytocinergic signaling as a mechanism by which it accomplishes some of its many roles. In this study, we used an established human RPE cell line, a HEK293 heterologous OXTR expression system, and pharmacological inhibitors of Ca2+ signaling to demonstrate that OXTR utilizes capacitative Ca2+ entry (CCE) mechanisms to sustain an increase in cytoplasmic Ca2+. These findings demonstrate how multiple functional outcomes of OXT-OXTR signaling could be integrated via a single pathway. In addition, the activated OXTR was able to inhibit the Kir7.1 channel, an important mediator of sub retinal waste transport and K+ homeostasis.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Oxytocin (OXT)-stimulated inhibition of Kir7.1 activity is through PIP 2 -dependent Ca 2+ response of the oxytocin receptor in the retinal pigment epithelium in vitro

York

Halbach

Chiu

et al. 2017

Cellular Signalling

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“…We have previously determined that cultured human fetal RPE cells express Rb+ sensitive Kir7.1 current similar to what we recorded from wild-type and carrier hiPSC-RPE cells. 19 In our hands, heterozygous expression of equal amounts of wild type and non-functional p.Trp53* mutant protein also does not influence cellular physiology outcome. 1 Given these findings, we reasoned that carrier hiPSC-RPE are a suitable control to compare test results of both gene restoration and translational read-through.…”

Section: Discussionmentioning

confidence: 59%

Gene augmentation and read-through rescue channelopathy in an iPSC-RPE model of congenital blindness

Shahi

Hermans

Sinha

et al. 2018

Preprint

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PurposeMutations in the KCNJ13 gene are known to cause Leber’s Congenital Amaurosis (LCA16), an inherited pediatric blindness. KCNJ13 gene encodes the Kir7.1 subunit protein which acts as a tetrameric inwardly rectifying potassium ion channel in the retinal pigment epithelium to maintain ionic homeostasis thereby allowing photoreceptors to encode visual information. We sought to determine if genetic approaches might be effective in treating blindness due to mutations in KCNJ13.MethodsWe developed patient-derived hiPSC-RPE carrying an autosomal recessive nonsense mutation in the KCNJ13 gene (c.158G>A, p.Trp53*). We performed biochemical and electrophysiology assays of Kir7.1 function. Both small molecule read-through drug and gene-therapy approaches were tested using this disease-in-a-dish approach.ResultsWe found that the LCA16 hiPSC-RPE had normal morphology but did not express a functional Kir7.1 channel and was unable to demonstrate normal physiology. Following read-through drug treatment, the LCA16 hiPSC cells were hyperpolarized by 30 mV and Kir7.1 current was restored. Similarly, loss-of-function of Kir7.1 channel was circumvented by lentiviral gene delivery to the hiPSC-RPE cells. In either approach, Kir7.1 protein was expressing normally with restoration of membrane potential and Kir7.1 current.ConclusionLoss-of-function mutation in Kir7.1 is a cause of LCA. Using either read-through therapy or gene augmentation, we rescued Kir7.1 channel function in patient-derived iPSC-RPE cells via a precision medicine approach.

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Region‐specific sex modulation of central oxytocin receptor by gut microbiota: An ontogenic study

Effah

Silva

Camarini

et al. 2021

Developmental Neurobiology

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Oxytocin (OT) is a developmentally important neuropeptide recognized to play a dominant role in social functioning and stress‐related behaviors, in a sex‐dependent manner. Nonetheless, the underlining factors driving OT and OT receptor (OTR) early brain development remain unclear. Recent evidence highlight the critical influence of gut microbiota and its bidirectional interaction with the brain on neurodevelopment via the gut microbiota‐brain axis. Therefore, we aimed to determine the impact of gut microbiota on the OTR system of the rat brain at different developmental stages in a pilot study. Quantitative OTR [125I]‐OVTA autoradiographic binding was carried out in the forebrain of male and female conventional (CON) and germ‐free (GF) rats at postnatal days (PND) 8, 22, and 116–150. OTR binding was also assessed in the eyes of PND 1 and PND 4 GF female rats. Significant “microbiota × sex × region” interaction and age‐dependent effects on OTR binding were demonstrated. Microbiota status influenced OTR levels in males but not females with higher levels of OTR observed in GF versus CON rats in the cingulate, prelimbic, and lateral/medial/ventral orbital cortex, and septum across all age groups, while sex differences were observed in GF, but not in CON rats. Interestingly, OTRs present in the eyes of CON rats were abolished in GF rats. This is the first study to uncover a sex‐specific role of gut microbiota on the central OTR system, which may have implications in understanding the developmental neuroadaptations critical for behavioral regulation and the etiology of certain neurodevelopmental disorders.

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Oxytocin Expression and Function in the Posterior Retina: A Novel Signaling Pathway

Cited by 24 publications

References 29 publications

Oxytocin (OXT)-stimulated inhibition of Kir7.1 activity is through PIP 2 -dependent Ca 2+ response of the oxytocin receptor in the retinal pigment epithelium in vitro

Oxytocin (OXT)-stimulated inhibition of Kir7.1 activity is through PIP 2 -dependent Ca 2+ response of the oxytocin receptor in the retinal pigment epithelium in vitro

Gene augmentation and read-through rescue channelopathy in an iPSC-RPE model of congenital blindness

Region‐specific sex modulation of central oxytocin receptor by gut microbiota: An ontogenic study

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