Vladimir J. Kefalov, Ph.D.
Ophthalmology and Visual Sciences
We are a sensory neurobiology lab interested in the function of mammalian rod and cone photoreceptors. These sensory neurons use a prototypical G-protein signaling cascade to convert light into electric signal as the first step in visual perception. Our studies involve the use a battery of state-of-the-art tools, from single-cell and isolated retina electrophysiological recordings, to in vivo electroretinogram and behavior experiments with wild type and genetically modified mice. While the emphasis of our studies is on our daytime photoreceptors, the cones, we are also investigating some aspects of rod phototransduction. In addition, we are interested in the mechanisms of neurodegeneration in the retina and are working on developing pharmacological and gene-therapy tools for preventing photoreceptor cell death. Currently, we are engaged in three separate NIH-funded projects:
1. Mechanisms of cone dark adaptation
Cone photoreceptors function under daylight conditions and are essential for color perception and vision with high temporal and spatial resolution. One of the fundamental mysteries of the human visual system is the continuous function of cone photoreceptors in bright daylight and t heir rapid dark adaptation. As visual pigment is destroyed, or bleached, by light, cones require its rapid regeneration, which in turn involves rapid recycling of the pigment’s chromophore. We have recently demonstrated the function of a novel pathway in the amphibian, mouse, primate, and human retinas that promotes such rapid recycling of chromophore, pigment regeneration, and dark adaptation specifically in cones, but not in rods. This mechanism is independent of the pigment epithelium and instead relies on the glial (Mller) cells in the retina. We are currently characterizing this pathway in the mammalian retina and the mechanisms that restrict its function to cones. This research is funded by an RO1 grant from the National Eye Institute.
2. Mechanisms of cone light adaptation
The ability of cones to adapt over a wide range of light intensities is critical for their function as our daytime photoreceptors. Their wide dynamic range implies the existence of powerful adaptation mechanisms of the cone phototransduction cascade. Photoreceptor light adaptation is mediated by the decline in calcium upon photoactivation. However, the molecular mechanisms by which lowering calcium exerts negative feedback on cone phototransduction are not known. Using physiological tools and genetically modified mice, we are investigating how mammalian cone phototransduction is modulated by the calcium-binding proteins recoverin and guanylyl cyclase activating proteins (GCAPs). We are investigating how the deletion of each of these proteins affects the photoresponse gain and kinetics in mouse cones in darkness as well as their ability to adapt to background light. This research is funded by an R21 grant from the National Eye Institute.
3. Pharmacological treatments of retinal degeneration
Mutations in several of the genes involved in the turnover of chromophore can cause a delayed clearance of all-trans retinal from photoreceptors following exposure to bright light. Both all-trans retinal and its aggregate N-retinylidene-N-retinylethanolamine (A2-E) are believed to cause retinal degenerative disorders. In humans, mutations in the photoreceptor-specific ABC chromophore transporter (ABCR, also known as ABCA4), located in the photoreceptor outer segments, lead to impaired visual function, including slower rod dark adaptation and accumulation of A2-E and lipofuscin. Such mutations have been associated with visual disorders including autosomal recessive Stargardt disease and cone-rod dystrophy. As part of a multi-institutional project, we are currently working on developing pharmacological treatments targeting the turnover of chromophore in an effort to prevent its accumulation and retinal degeneration. This research is funded by an R24 grant from the National Eye Institute.
Kolesnikov, A.V., Maeda, A., Tang, P.H., Imanishi, Y., Palczewski, K., Kefalov, V.J. (2015) Retinol dehydrogenase 8 and ATP-binding cassette transporter 4 modulate dark adaptation of M-cones in mammalian retina. J Phyiol [in press].
Vinberg, F., Wang, T., Molday, R.S., Chen, J., Kefalov, V.J. (2015) A new mouse model for stationary night blindness with mutant Slc24a1 explains the pathophysiology of the associated human disease. Hum Mol Genet [in press].
Wang JS, Nymark S, Frederiksen R, Estevez ME, Shen SQ, Corbo JC, Cornwall MC, Kefalov VJ. Chromophore supply rate-limits Mammalian photoreceptor dark adaptation. J Neurosci. 2014 34(34):11212-21. PMID: 25143602
Xue, Y, Shen, S.Q., Jui, J, Rupp, A.C., Byrne, L.C., Hattar, S, Flannery, J.G, Corbo, J.C., Kefalov, V.J. (2015) CRALBP supports the mammalian retina visual cycle and cone vision. J Clin Invest 125:727-738.
Sakurai K., Chen J., Khani S., Kefalov V.J. (2015) Regulation of mammalian cone phototransduction by recoverin and rhodopsin kinase. J Biol Chem 290:9239-9250.
Vinberg, F., Kefalov, V.J. (2015) Simultaneous ex vivo functional testing of two retinas by in vivo electroretinogram system. JoVE 6: doi: 10.3791/52855.
Palczewska, G.*, Vinberg, F. *, Stremplewski, P. *, Bircher, M.P. *, Salomǁ, D., Komar, K., Zhang, J., Cascella, M.#, Wojtkowski, M.#, Kefalov, V.J.#, Palczewski, K.# (2014) Human infrared vision is triggered by two-photon chromophore isomerization. Proc Natl Acad Sci USA 111:E5445-5454.
Last Updated: 11/9/2015 3:13:08 PM
G-protein mediated signaling in retinal rod photoreceptors. Abbreviations: ROS, rod outer segment; RIS, rod inner segment; N, nucleus; ST, synaptic terminal; R*, photoactivated rhodopsin; ? and ??, transducin subunits; PDE, phosphodiesterase; GTP, guanosine triphosphate; GDP, guanosine diphosphate; cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; Pi, inorganic phosphate.