Optogenetic user s guide to Opto-GPCRs

Kleinlogel, Sonja

doi:10.2741/4421

Cited by 28 publications

(27 citation statements)

References 46 publications

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“…Nonetheless, ChR2 variants that had been developed for improved clinical applicability with increased light response amplitudes and slowed kinetics will increase the overall cell depolarization and Ca 2+ transmittance, which renders them potentially more toxic. 1, 2 Recently developed Opto-GPCRs that are coupled to native cellular pathways 3, 9, 29, 30 and are 1000-fold more light sensitive may therefore present alternative safer tools for the treatment of neurological disorders in human patients.…”

Section: Discussionmentioning

confidence: 99%

Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad

et al. 2016

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Channelrhodopsin-2 (ChR2) has become a celebrated research tool and is considered a promising potential therapeutic for neurological disorders. While making its way into the clinic, concerns about the safety of chronic ChR2 activation have emerged; in particular as the high-intensity blue light illumination needed for ChR2 activation may be phototoxic. Here we set out to quantify for the first time the cytotoxic effects of chronic ChR2 activation. We studied the safety of prolonged illumination on ChR2(D156A)-expressing human melanoma cells as cancer cells are notorious for their resistance to killing. Three days of illumination eradicated the entire ChR2(D156A)-expressing cell population through mitochondria-mediated apoptosis, whereas blue light activation of non-expressing control cells did not significantly compromise cell viability. In other words, chronic high-intensity blue light illumination alone is not phototoxic, but prolonged ChR2 activation induces mitochondria-mediated apoptosis. The results are alarming for gain-of-function translational neurological studies but open the possibility to optogenetically manipulate the viability of non-excitable cells, such as cancer cells. In a second set of experiments we therefore evaluated the feasibility to put melanoma cell proliferation and apoptosis under the control of light by transdermally illuminating in vivo melanoma xenografts expressing ChR2(D156A). We show clear proof of principle that light treatment inhibits and even reverses tumor growth, rendering ChR2s potential tools for targeted light-therapy of cancers.

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Section: Discussionmentioning

confidence: 99%

Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad

et al. 2016

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“…As already mentioned, combining these makes it possible to control different effects using different light colors (Stark et al, 2012 ). More recently, several cellular control methods have been developed around the possibility to modulate G-proteins (Kleinlogel, 2016 ) thus opening a new branch of optogenetics with new applications in perspective. Alternatively, genes for endo-cellular molecules (for example genes expressing fluorescent proteins for bio-sensing Enterina et al, 2015 ) as well as various ion channels can be integrated in the cell genome.…”

Section: Optogeneticsmentioning

confidence: 99%

And Then There Was Light: Perspectives of Optogenetics for Deep Brain Stimulation and Neuromodulation

et al. 2017

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Deep Brain Stimulation (DBS) has evolved into a well-accepted add-on treatment for patients with severe Parkinsons disease as well as for other chronic neurological conditions. The focal action of electrical stimulation can yield better responses and it exposes the patient to fewer side effects compared to pharmaceuticals distributed throughout the body toward the brain. On the other hand, the current practice of DBS is hampered by the relatively coarse level of neuromodulation achieved. Optogenetics, in contrast, offers the perspective of much more selective actions on the various physiological structures, provided that the stimulated cells are rendered sensitive to the action of light. Optogenetics has experienced tremendous progress since its first in vivo applications about 10 years ago. Recent advancements of viral vector technology for gene transfer substantially reduce vector-associated cytotoxicity and immune responses. This brings about the possibility to transfer this technology into the clinic as a possible alternative to DBS and neuromodulation. New paths could be opened toward a rich panel of clinical applications. Some technical issues still limit the long term use in humans but realistic perspectives quickly emerge. Despite a rapid accumulation of observations about patho-physiological mechanisms, it is still mostly serendipity and empiric adjustments that dictate clinical practice while more efficient logically designed interventions remain rather exceptional. Interestingly, it is also very much the neuro technology developed around optogenetics that offers the most promising tools to fill in the existing knowledge gaps about brain function in health and disease. The present review examines Parkinson's disease and refractory epilepsy as use cases for possible optogenetic stimulation therapies.

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“…Like Opto-RTKs, work to establish a photoactivated set of GPCRs is a burgeoning field 86 . Specifically, Opto-α 1 AR and Opto-β 2 AR adrenergic receptors 53 termed Opto-XRs were formed by engineering a bovine G(t)-protein coupled rhodopsin stimulated by green light (504nm) by replacing its intracellular loops with those of the Gq-coupled α 1a -adrenergic receptor (α 1 AR) or Gs-coupled β 2 -adrenergic receptor (β 2 AR).…”

Section: Photoactuatorsmentioning

confidence: 99%

Genetically Encoded Photoactuators and Photosensors for Characterization and Manipulation of Pluripotent Stem Cells

Pomeroy¹,

Nguyen²,

Hoffman³

et al. 2017

Theranostics

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Our knowledge of pluripotent stem cell biology has advanced considerably in the past four decades, but it has yet to deliver on the great promise of regenerative medicine. The slow progress can be mainly attributed to our incomplete understanding of the complex biologic processes regulating the dynamic developmental pathways from pluripotency to fully-differentiated states of functional somatic cells. Much of the difficulty arises from our lack of specific tools to query, or manipulate, the molecular scale circuitry on both single-cell and organismal levels. Fortunately, the last two decades of progress in the field of optogenetics have produced a variety of genetically encoded, light-mediated tools that enable visualization and control of the spatiotemporal regulation of cellular function. The merging of optogenetics and pluripotent stem cell biology could thus be an important step toward realization of the clinical potential of pluripotent stem cells. In this review, we have surveyed available genetically encoded photoactuators and photosensors, a rapidly expanding toolbox, with particular attention to those with utility for studying pluripotent stem cells.

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Optogenetic user s guide to Opto-GPCRs

Cited by 28 publications

References 46 publications

Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad

Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad

And Then There Was Light: Perspectives of Optogenetics for Deep Brain Stimulation and Neuromodulation

Genetically Encoded Photoactuators and Photosensors for Characterization and Manipulation of Pluripotent Stem Cells

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