Molecular

RECENT WORK CENTERED ON MOLECULAR FUNCTION

Melanopsin Tristability for Sustained and Broadband Phototransduction

Mammals rely upon three ocular photoreceptors to sense light: rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs). Rods and cones resolve details in the visual scene. Conversely, ipRGCs integrate over time and space, primarily to support "non-image" vision. The integrative mechanisms of ipRGCs are enigmatic, particularly since these cells use a phototransduction motif that allows invertebrates like Drosophila to parse light with exceptional temporal resolution. Here, we provide evidence for a single mechanism that allows ipRGCs to integrate over both time and wavelength. Light distributes the visual pigment, melanopsin, across three states, two silent and one signaling. Photoequilibration among states maintains pigment availability for sustained signaling, stability of the signaling state permits minutes-long temporal summation, and modest spectral separation of the silent states promotes uniform activation across wavelengths. By broadening the tuning of ipRGCs in both temporal and chromatic domains, melanopsin tristability produces signal integration for physiology and behavior.

Shown at the top is an electrophysiological recording from an ipRGC. A pulse of short-wavelength light triggers activation that continues in darkness for almost twenty minutes, at which point it is terminated by a pulse of long-wavelength light. The cell can be switched on and off repeatedly in this fashion. Depicted below is our understanding of how the melanopsin molecule drives this cellular response. The molecule appears to be a three-way switch, with two OFF positions (the legs of the inverted "v") and one ON position (the apex). Short wavelengths of light "push" most strongly on the OFF positions (switching the molecule to the ON position). The ON position is stable, such that it can drive cellular activation for an extended period. Long wavelengths push most strongly on the ON position (switching the molecule to either of the OFF positions). Each OFF position is pushed best by different wavelengths (cyan for one and violet for the other). When ipRGCs have been kept in darkness (but not light) for an extended period of time, only the cyan state is detectable. Thus, it is likely that melanopsin reverts to this state using a pathway that is independent of light.

Some questions raised by this work: whether the two silent states have differential effects on the cell, what the structural determinants of tristability are, whether parameters of tristability in the melanopsins of various species are differentially tuned, and if other visual pigments are also multistable.