The goal of the proposed research is to decipher unconventional roles for opsins. This project builds on our recent discoveries that opsins are not just light sensors, and offers to transform our understanding of the sensory roles of these receptors, which were discovered nearly 150 years ago. Rather than functioning exclusively in photosensation, we suggest that opsins are broadly required sensory receptors, potentially as wide-ranging as TRP channels. Opsins are expressed in a diverse array of cell types and tissues outside of the visual system. Currently, the roles of these extra-ocular opsins are largely unknown. The goal of the present proposal is to exploit state-of-the-art tools available for use with the fruit fly, Drosophila melanogaster, to identify a range of roles for opsins. The proposed research brings to bear a wide set of in vivo and in vitro electrophysiological techniques, in vivo Ca2+-imaging, behavioral assays, cell biology and molecular genetics to address a variety of unconventional roles for opsins.
The first aim i s to clarify a role for an opsin in the central brain.
Aim 1 will test the idea that a previously uncharacterized Drosophila opsin, Rh7, functions as a photosensor in circadian pacemaker neurons in the brain, and is required for normal circadian photoentrainment.
This aim will address the hypothesis that Rh7 promotes entrainment to low levels of light by coupling to the same type of phototransduction cascade that operates in known photoreceptor cells.
Aim 2 will test the iconoclastic hypothesis that Rh7 also has a light-independent function in taste. We propose to identify the signaling proteins that couple to Rh7 in gustatory receptor neurons, which may be the same as those that function in phototransduction. We posit that the primordial function of opsins was in chemosensation. In addition to gustation, another ancient chemical sense is olfaction.
Aim 3 will investigate a potential role for another opsin in olfaction.
Aim 4 investigates the functions of opsins in thermosensation. Experiments are outlined to test whether opsin-dependent signaling cascades are required in larval temperature discrimination to promote thermal adaptation, in addition to amplifying small temperature differences. Based on recent preliminary data, aim 4 will address the question as to whether opsins also enable adult flies to select their preferred temperature in the comfortable range. Mammalian opsins are expressed in a broad range of extra- retinal tissues. The proposed experiments will provide a deeper understanding of the biological functions of extra-ocular opsins, and form the conceptual basis for investigating unconventional roles for mammalian opsins. Because G-protein coupled receptors similar to opsins are the most successful drug targets, non-visual opsins may provide effective new possibilities for drug development. Currently, drugs are in development to treat retinal degenerations that result from dominant mutations affecting rhodopsin. Understanding the diversity of roles for opsins is also an important step towards selecting drugs that have minimal effects on non-visual opsins, so as to reduce unintended side effects of these therapies.
The light receptor rhodopsin is critical for vision, and mutations in rhodopsin lead to common forms of retinal degeneration. The aim of the proposed research is to reveal additional sensory roles for opsins, which have eluded detection since the discovery of rhodopsin more than 100 years ago. ~25% of all drugs are directed against opsin-like receptors (called GPCRs), making this class of protein the most successful drug target known. Therefore, the identification of new roles for opsins provides the potential for identifying new classes of drugs to treat disease.
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