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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    735—Retina: Photoreceptors

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    735.13: A mechanism for sustained and broadband signaling by a ganglion cell photoreceptor

    Location: Halls B-H

    ">*A. J. EMANUEL1,2, M. H. DO1,3;
    1F. M. Kirby Neurobio. Ctr., Boston Children's Hosp., Boston, MA; 2Program in Neurosci., Harvard Univ., Boston, MA; 3Neurol., Harvard Med. Sch., Boston, MA

    Abstract Body: Intrinsically photosensitive retinal ganglion cells (ipRGCs) influence diverse functions in mammals, such as acute regulation of sleep and synchronization of circadian rhythms with the solar day. We have used patch-clamp electrophysiology in the murine retina to examine ipRGC light responses. We report that a brief pulse of light can activate ipRGCs for many minutes, and that this persistent response can be deactivated by a subsequent pulse of long-wavelength light. This phenomenon survives voltage clamp and pharmacological block of synaptic transmission. Thus, ipRGC phototransduction appears to have silent and signaling states that are interconverted by light. Biochemical experiments by others indicate that melanopsin, the photopigment of ipRGCs, also has states that are interconverted by light (Matsuyama et al., Biochemistry 51:5454-5462, 2012). These states are “melanopsin” (with a peak sensitivity at 467 nm), “metamelanopsin” (476 nm), and "extramelanopsin" (446 nm). To determine if these molecular states account for the physiological states that we observed, we systematically analyzed how exposure to various wavelengths of light affects ipRGC phototransduction. Our data suggest that all three states of melanopsin govern the physiology of ipRGCs. Notably, we found that producing a large fraction of extramelanopsin with long-wavelength light causes ongoing phototransduction to deactivate, which leads to a rise in sensitivity. In addition, the action spectrum of ipRGCs shifts from having a peak near that of melanopsin (471 nm) to one near that of extramelanopsin (454 nm). We conclude that, within ipRGCs, melanopsin principally has two silent states that interconvert with one signaling state during illumination. We suggest three implications of this finding. First, activation from both melanopsin and extramelanopsin broadens ipRGC spectral sensitivity. Second, equilibration of melanopsin among silent and signaling states helps to preserve ipRGC photosensitivity during illumination. Third, the thermal stability of melanopsin's signaling state increases temporal summation by ipRGCs. In summary, melanopsin tristability appears to promote continuous signaling by ipRGCs over a large part of the visible spectrum.

    Lay Language Summary: Our research indicates that a population of photoreceptors in the mammalian retina--the melanopsin cells--capture light with a mechanism that is unique but homologous to that used by invertebrates such as flies and horseshoe crabs. Specifically, the light receptor of these cells, melanopsin, switches among three stable states. This “tristability” causes melanopsin cells to respond with an unusual degree of similarity to different colors of illumination, and in a sustained fashion.
    Light sensing by melanopsin cells exerts a widespread influence on physiology, particularly by regulating it in accordance with day-night rhythms. Dysregulation of these biological rhythms, such as from artificial lighting at night, has been linked to maladies such as obesity and cancer. At the same time, artificial light can be used therapeutically during the day, as in the treatment of seasonal affective disorder. Blue light is considered especially potent in both regards due to its effectiveness in activating melanopsin. In contrast, we present evidence that virtually all light sources are comparable in their activation of melanopsin because of tristability. Our findings allow for the improved use of light to promote health.
    To our knowledge, we present the first description of tristability and its consequences in any photoreceptor. In addition, the nature of the melanopsin molecule has been controversial for more than a decade. Our analysis suggests that melanopsin is tristable and that this tristability accounts for many of the disparate findings that underlie disagreement in the scientific community.
    Our research entailed recording the electrical activity of melanopsin cells while exposing them to light of precise colors and intensities. We identified melanopsin cells for study using a genetically-engineered mouse line in which these cells are marked with a fluorescent protein. We isolated their intrinsic light responses by applying drugs to block signaling from other cells.
    We made two principal findings. The first is that melanopsin cells respond to light as if they possess two light-sensitive receptors, each with a different color preference. By comparing the properties of the cells with prior knowledge of melanopsin biochemistry, we connected this property to tristability of the melanopsin molecule. The melanopsin molecule activates from two states (each with a different color preference) to a single active state. This allows melanopsin cells to respond more evenly across the visible range of colors.
    The second finding is that melanopsin cells can remain activated for many minutes even after a brief (milliseconds) pulse of light because the active state is stable. This sustained activation allows them to smooth fluctuations in light intensity over time, thereby providing an accurate representation of the ambient light level.
    Light is a key regulator of mammalian physiology. We have dissected part of the mechanism by which light is translated into biological signals by melanopsin cells. Future work will delineate additional properties and mechanisms of these photoreceptors, which govern diverse functions that range from the acute switching of sleep/wake state to the circadian clock.