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
In collaboration with Dr. Mike Varnum, we are also investigating the
regulation and trafficking of cyclic nucleotide-gated ion channels.
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.
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.
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.
. 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.
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
Morgans, C.W., Liu, W., Wensel, T.G. Bearnot, B., Perez-Leon, J.A.,
Brown, R.L., & Duvoisin, R.M. (2007) Gb
complexes co-localize with mGluR6 in retinal ON-bipolar cells;
European J. Neurosci
. 26: 2899-2905.