Many aspects of mammalian physiology and behavior exhibit a daily 24 hour rhythm. These daily oscillations are circadian rhythms and are controlled by a brain structure known as the suprachiasmatic nucleus (SCN). The mammalian circadian clock is constantly being reset by the onset of environmental light. Light entrainment of the clock requires input from the retina, which communicates with the SCN via the axonal projections of a small subset of retinal ganglion cells (RGCs). Surprisingly, rod and cone photoreceptors are not required; instead, RGCs that project to the SCN appear to function as autonomous circadian photoreceptors as they exhibit light responses independent of rod- and cone-driven synaptic input. Interestingly, the action spectrum of the light-evoked depolarization of these photosensitive retinal ganglion cells is described by a photopigment with a wavelength of maximum absorbance of 484 nm.
Melanopsin, a novel opsin-like protein expressed in some of the retinal ganglion cells that project to the SCN, appears to be the elusive circadian photopigment based on several lines of evidence. Melanopsin is expressed in the light-sensitive RGCs and disruption of the melanopsin gene in mice abolishes the intrinsic light response of the SCN-projecting RGCs and impairs circadian entrainment. However, these elegant experiments do not address the question of whether melanopsin is a photopigment directly responsible for generating the light response, or simply an isomerase required for chromophore regeneration on a separate photopigment. Data from the Robinson laboratory was the first to demonstrate that melanopsin does indeed form a functional photopigment. This led to the hypothesis that melanopsin has a unique role in mammalian RGCs involved in circadian photoentrainment and the light-activated melanopsin triggers a G-protein cascade that underlies the photic response generated by these melanopsin-containing RGCs. Based on its homology with invertebrate opsins, the prediction is that melanopsin activates a Gq-based signaling pathway. This grant proposes to use molecular and biochemical approaches to further characterize melanopsin.
The proposed research is significant because melanopsin is a novel and newly discovered mammalian retinal visual pigment involved in circadian photoentrainment. It appears to have many properties similar to visual pigments that have been characterized in rhabdomeric invertebrate eyes. This makes this pigment unique among mammalian visual pigments and fascinating to study. The approaches proposed in this grant are novel. The Robinson lab is the only laboratory that has taken a decidedly molecular and biochemical approach to study this visual pigment, and is poised to make significant progress on understanding this visual pigment within the next two years.
Broader Impacts: The P.I of this grant is acutely aware of NSF's commitment to education and the development of underrepresented groups in the United States' Scientific workforce in the 21 st century. The P.I is currently a co-P.I. on a NSF institutional ADVANCE award to UMBC which as an institution is committed to the inclusion of both women and minorities in science. The P.I. has established an inclusive laboratory environment where underrepresented students, both graduate and undergraduate, have a positive research experience. Part of research described in this grant will be conducted by an African-American male. When possible, these undergraduates will include talented minority and women undergraduates identified form the nationally recognized Meyerhoff Scholars Program. The P.I. will also continue the practice of disseminating research results to the public through public lectures and visits to local high schools.
