Small-molecule antagonists of melanopsin-mediated phototransduction

Jones, Kenneth A.; Hatori, Megumi; Mure, Ludovic S.; Bramley, Jayne R.; Artymyshyn, Roman; Hong, Sang Phyo; Marzabadi, Mohammad R.; Zhong, Huailing; Sprouse, Jeffrey; Zhu, Qing; Hartwick, Andrew T. E.; Sollars, Patricia J.; Pickard, Gary E.; Panda, Satchidananda

doi:10.1038/nchembio.1333

Cited by 65 publications

(66 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The involvement of ipRGCs in photophobia has been described in mice. [24][25][26] It has been confirmed that the pupil diameter increases when ipRGC and rod excitation is at a minimum. 27 Furthermore, there is strong evidence of an inhibiting influence of S-cones on ipRGCs.…”

Section: Discussionmentioning

confidence: 61%

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

Lisowska

Lisowski

Kelbsch

et al. 2017

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

Citation: Lisowska J, Lisowski L, Kelbsch C, et al. Development of a chromatic pupillography protocol for the first gene therapy trial in patients with CNGA3-linked achromatopsia. Invest Ophthalmol Vis Sci. 2017;58:127458: -128258: . DOI:10.1167 PURPOSE. To establish a feasible and sensitive pupillographic protocol to assess outer and inner retinal function for the first gene therapy trial in achromatopsia patients (ACHM) with mutations in CNGA3.METHODS. Twenty-seven CNGA3-ACHM patients and 22 age-matched control subjects were tested using chromatic pupillography. Three different protocols were established to assess the pupillary light reflex parameters and to create the final protocol. In the individual protocols, various stimulus parameters (i.e., intensity, duration, wavelength, adaptation states) were applied to evaluate the impact of these stimuli on the pupillary response in untreated ACHM patients.RESULTS. In the light-adapted conditions, CNGA3-ACHM patients showed significantly reduced maximal amplitudes compared with the control group when using a 1-second high intensity (28-lux corneal illumination) blue or red stimulus (P < 0.005). In the dark-adapted conditions, CNGA3-ACHM patients unexpectedly revealed significantly increased maximal amplitudes when stimulating with red (1 second) or blue (4 ms and 1 second) stimuli of low intensity (0.01-lux corneal illumination; P < 0.05). Pupil responses of CNGA3-ACHM patients after high intensity (28 lux) red and blue 1-second stimuli were within the normal range.CONCLUSIONS. Chromatic pupillography demonstrated significant reduced pupil responses to stimuli addressing primarily cone function, an increased sensitivity to rod-favoring stimuli and evidence for disinhibition of intrinsically photosensitive retinal ganglion cells in CNGA3-ACHM patients. A final protocol was established based on these findings. These conclusions may be useful for the objective assessment of efficacy gained by gene therapy or other innovative interventions in this hereditary retinal disorder.Keywords: chromatic pupillography, achromatopsia, CNGA3, ipRGC A chromatopsia (ACHM) is an inherited autosomal recessive congenital retinal disease, with a prevalence of one in 30,000.1 The most characteristic symptom is the inability to discriminate colors due to the loss of cone photoreceptor function. Achromatopsia patients also suffer from severely reduced visual acuity, nystagmus, and photophobia. 2 Rarely, individuals have incomplete ACHM, in which one or more cone types may be partially functioning. 3 The clinical findings of incomplete ACHM are similar to the complete form, but milder. Fundus examination is usually normal, and electrophysiological testing demonstrates absent cone responses and normal or near-normal rod function. [2][3][4][5] To date, mutations in six genes have been shown to be associated with ACHM: CNGA3 and CNGB3 encode the a and b subunits of the cGMP-gated cation channel, 6 GNAT2 the a subunit of the cone-specific G-protein transducing, 7 PDE6C and PDE6H code for the ...

show abstract

Section: Discussionmentioning

confidence: 61%

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

Lisowska

Lisowski

Kelbsch

et al. 2017

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

show abstract

“…Previous studies have found the absorption maxima of purified melanopsins and the maximal spectral sensitivity of melanopsin-expressing cultured cells are both around 480 nm (13, 14, 16 -21). Although some G q -independent signaling by melanopsin has been suggested (22), a variety of melanopsins are reported to show light-dependent G q activation in vivo and in vitro (14,17,18,(23)(24)(25)(26), consistent with their high sequence similarity with the invertebrate visual pigments, which also use G q -dependent signaling (7,9) (Fig. 1A).…”

mentioning

confidence: 53%

“…Because melanopsins are coupled with G q -type G proteins, light-dependent G q activation by melanopsin can be detected as an increase in the Ca 2ϩ -activated Cl Ϫ current (14, 39,40). To detect the difference in the retinal release rate from melanopsin, melanopsin-expressing oocytes were treated with retinal and subsequently incubated at 37°C in the dark for 90 min in the presence or absence of a melanopsin-specific antagonist AA92593 (24). A previous study has shown that the antagonist can bind to the retinal-free form of melanopsin and block retinal binding to the protein, leading to reduction of light-dependent current by melanopsin (24).…”

Section: Retinal Release From Melanopsin Molecules In Cell Membranesmentioning

confidence: 99%

Retinal Attachment Instability Is Diversified among Mammalian Melanopsins

Tsukamoto

Kubo

Farrens

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Melanopsin is involved in non-visual photoreception in mammals, but molecular characteristics underlying these non-visual functions are unclear. Results: Stability of the bond with the retinal chromophore is weakened and diversified in mammalian melanopsins. Conclusion: Mammalian melanopsins have acquired characteristics suited for their non-visual functions. Significance: The weaker retinal attachment in melanopsin may contribute to the functional tuning of non-visual photoreception in mammals.

show abstract

“…Indeed, it has been suggested that the mood stabilizer lithium may have a circadian mechanism of action [97], and casein kinase 1δ/ε inhibitors have shown promise in pre-clinical animal models of AUD [121] and BD [122]. Additional compounds have been developed to target the ROR/REV-ERB nuclear receptors [123], CRYs [124], melanopsin-containing photoreceptors [125] and other complex mechanisms [123] that strongly affect circadian rhythms, but remain poorly characterized with respect to brain effects and potential as treatments for psychiatric conditions. Suppression of GC synthesis with metyrapone counteracts the elevations in GC levels associated with environmental changes, and accelerates the clock's adaptation, potentially offering the means to better adjust the circadian system to stressful environments [23].…”

Section: Discussionmentioning

confidence: 99%

Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders

Landgraf

McCarthy

Welsh

2014

Curr Psychiatry Rep

149

100

View full text Add to dashboard Cite

Many psychiatric disorders are characterized by circadian rhythm abnormalities including disturbed sleep/wake cycles, changes in locomotor activity, and abnormal endocrine function. Animal models with mutations in circadian "clock genes" commonly show disturbances in reward processing, locomotor activity and novelty seeking behaviors, further supporting the idea of a connection between the circadian clock and psychiatric disorders. However, if circadian clock dysfunction is a common risk factor for multiple psychiatric disorders, it is unknown if and how these putative clock abnormalities could be expressed differently, and contribute to multiple, distinct phenotypes. One possible explanation is that the circadian clock modulates the biological responses to stressful environmental factors that vary with an individual's experience. It is known that the circadian clock and the stress response systems are closely related: Circadian clock genes regulate the physiological sensitivity to, and rhythmic release of glucocorticoids (GC). In turn, GCs have reciprocal effects on the clock. Since stressful life events or increased vulnerability to stress are risk factors for multiple psychiatric disorders including posttraumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BD), major depressive disorder (MDD), alcohol use disorder (AUD) and schizophrenia (SCZ), we propose that modulation of the stress response is a common mechanism by which circadian clock genes affect these illnesses. Presently, we review how molecular components of the circadian clock may contribute to these six psychiatric disorders, and present the hypothesis that modulation of the stress response may constitute a common mechanism by which the circadian clock affects multiple psychiatric disorders.

show abstract

Small-molecule antagonists of melanopsin-mediated phototransduction

Cited by 65 publications

References 32 publications

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

Retinal Attachment Instability Is Diversified among Mammalian Melanopsins

Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders

Contact Info

Product

Resources

About