It is now clear that the mammalian retina has at least one other photoreceptor class besides rods and cones, consisting of a subpopulation of retinal ganglion cells (RGCs) that express the pigment melanopsin (OPN4) and are intrinsically photosensitive (ipRGCs). These cells project predominantly to non-image-vision centers in the brain, serving functions such as circadian photoentrainment and pupillary light reflex. At the same time, ipRGCs project moderately to the brain's image-vision centers, presumably serving subtle image- forming visual functions such as possibly providing information about absolute light intensity in the visual scene. IpRGCs comprise at least 5 subtypes, M1-M5, which differ in the level of melanopsin content, photosensitivity, somatic and dendritic-field size, exact locations of their dendritic arborizations in the retina's inner plexiform layer, and the detailed locations of their axonal projections in the respective brain targets. To fully understand the ipRGC system, it is first and foremost important to know in detail their light- response properties and the underlying mechanisms. In recent years, we have made great progress in understanding M1-ipRGCs, including the molecular identities of several key phototransduction components. Specifically, this signaling pathway closely resembles in motif that found in fly-eye photoreceptors. Recently, we have made the exciting discovery of yet another phototransduction pathway in ipRGCs. This grant application constitutes a continuation of these successful investigations. Aim 1 is to establish the details of the second phototransduction pathway discovered by us, and to know the relative importance of the two signaling pathways. We would also like to complete the phototransduction pathway in M1-ipRGCs by establishing the molecular identity of the G protein involved. Aim 2 is to establish the details of light-response termination in ipRGCs, focusing on potential melanopsin phosphorylation, arrestin binding to melanopsin, and G-protein deactivation. Aim 3 is to study the intensity-response relation and the response kinetics of M2- and M4-ipRGCs, to detect/estimate their single-photon-response amplitudes and the melanopsin density in the membrane, as well as to measure their respective light-signaling threshold in order to assess their efficiency in signaling absorbed light. The overall goal is to compare/contrast M1- (already known), M2- and M4-cells. These properties may have differential significance with respect to the specific functions and neuronal circuitry associated with the different subtypes. In summary, ipRGCs are important for non-image vision and subtle aspects of image vision. Therefore, learning in detail how they function is of fundamental importance to vision in both health and disease.