College of Veterinary Medicine

Research in IPN

R. Lane Brown, Ph.D.


  

Associate Professor
E-Mail: brownla@vetmed.wsu.edu
Office: VBR 371
Phone: (509) 335-3390

Research in the Brown lab is primarily focused on three projects studying different aspects of retinal physiology and cell biology.

1. Generation of retinal signals for circadian entrainment.

Many physiological and behavioral rhythms, including the sleep-wake cycle, body temperature, and hormone levels, oscillate with a period of approximately 24 hours. In mammals, these circadian rhythms are driven by an autonomous master pacemaker located in the hypothalamus.

Like an old watch, however, this internal clock does not keep perfect time, and it must be reset each morning by the light of day, a process termed circadian photoentrainment. Proper synchronization of our internal clock with the external environment is essential for optimal physical and mental performance, as evidenced by the malaise of jet-lag and shift work.

In mammals, input from the retina is required for circadian photoentrainment. Surprisingly, however, classical rod- and cone photoreceptors are not required; instead, this function is mediated by a small subset of retinal ganglion cells (RGCs), which communicate directly with the circadian pacemaker, and express the novel photopigment, melanopsin, which triggers an intrinsic light response. Although the melanopsin-based signaling cascade remains somewhat elusive, it appears similar to phototransduction in invertebrate eyes. Over the next few years, the major goal of the research in my lab is to elucidate this signaling pathway using electrophysiology, biochemistry, and molecular genetics.

Although genetic deletion of melanopsin has been shown to eliminate the intrinsic light response in ipRGCs, the effect on circadian photoentrainment is surprisingly minor. Apparently, ipRGCs can also be stimulated by rod- and cone-driven synaptic input, and research over the past several years has revealed that these cells respond to both excitatory and inhibitory neurotransmitters. Over the next several years, we plan to identify the presynaptic cells using electrophysiology and trans-synaptic tracers.

2. Signaling mechanisms in retinal bipolar cells.

In the retina, visual information is segregated into pathways that respond to either increases or decreases in light intensity. Light stimulation decreases the rate of glutamate release from photoreceptor terminals. At the first synapse, two types of postsynaptic cells, the ON- and OFF-bipolar cells (BPCs), respond to synaptic glutamate with opposite polarity, thus establishing the opposing visual pathways that are maintained throughout the rest of the visual system. The ON-bipolar pathway originates with a unique metabotropic glutamate receptor, mGluR6, which is coupled via the G-protein, GO, to an unidentified cation channel. The light-induced decrease in glutamate causes an increase in channel activity and concomitant membrane depolarization. Despite intensive research over the past two decades, molecular identification of the majority of proteins involved in this signaling cascade remains elusive, and the long-term goal of this project is to identify the protein components of this signaling pathway.

The time course of all G-protein-mediated responses is determined by the kinetics of GTP hydrolysis by the G protein ? subunit, which is accelerated by interaction with RGS proteins. In photoreceptor outer segments, the light response is terminated by rapid deactivation of transducin by the G?5-RGS9-R9AP complex, and mutations in the genes encoding these proteins severely impair vision by slowing recovery after light flashes. Immunohistochemical data suggest that similar complexes are found in the dendritic tips of ON-BPCs. We hypothesize that the RGS7-G?5 and RGS11-G?5 complexes are critical components of the mGluR6 signal transduction pathway in ON-BPC dendrites, where they accelerate GTP hydrolysis by G?O. We will test this hypothesis over the next several years using an interdisciplinary approach, including electrophysiology, proteomics, and molecular genetics.

3. Physiology and cell biology of cyclic nucleotide-gated ion channels.

In collaboration with Dr. Mike Varnum, we are also investigating the regulation and trafficking of cyclic nucleotide-gated ion channels.

Biographical Information

R. Lane Brown graduated from the University of New Hampshire in 1985 with a B.S. (summa cum laude) in Biochemistry. In 1986, he joined the laboratory of Dr. Lubert Stryer in the Department of Cell Biology at Stanford University, where he first began his studies of retinal signal transduction, and graduated with a Ph.D. in 1991. After a post-doctoral fellowship with Dr. Jeff Karpen in the Department of Physiology and Biophysics at the University of Colorado School of Medicine, Lane started his independent research career in 1994 at the Neurological Sciences Institute, which became part of Oregon Health & Sciences University in 1998. Lane continued his career as an Associate Scientist at OHSU until 2007, when he joined IPN at Washington State University as an Assistant Professor.


Recent Publications

Zhang, J., Jeffrey, B.G., Morgans, C.W., Burke, N.S., Haley, T.L., Duvoisin, R.M., & Brown, R.L. (2010) RGS7 & 11 complexes accelerate the retinal ON-bipolar cell light response. Invest. Ophthalmol. & Vis. Sci. 51(2): 1121-9.

Jeffrey, B.G., Morgans, C.W., Puthessery, T., Wensel, T.G., Burke, N.S., Brown, R.L., & Duvoisin, R.M. (2010) R9AP stabilizes RGS-Gbeta5 and accelerates the early light response of ON-bipolar cells. Vis. Neurosci. 27(1-2): 9-17.

Morgans, C.W., Brown, R.L., & Duvoisin, R.M. (2010) TRPM1: the endpoint of the mGluR6 signal transduction cascade in retinal ON-bipolar cells. BioEssays 32(7): 609-614.

Ruggiero, L., Allen, C.N., Brown, R.L., & Robinson, D.W. (2010) Mice with early retinal degeneration show differences in neuropeptide expression in the suprachiasmatic nucleus. Behavioral & Brain Functions 6:36.

Morgans, C.W., Liu, W., Wensel, T.G. Bearnot, B., Perez-Leon, J.A., Brown, R.L., & Duvoisin, R.M. (2007) Gb5-RGS complexes co-localize with mGluR6 in retinal ON-bipolar cells; European J. Neurosci. 26: 2899-2905.

More Publications

Last Edited: May 02, 2013 10:46 AM   

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