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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 the Department of VCAPP at Washington State University as an
Assistant Professor.
Selected Publications
Warren,
E.J., Allen, C.N., Brown, R.L., & Robinson, D.W. (2003) Intrinsic light
responses of retinal ganglion cells involved in circadian entrainment;
European J. Neurosci. 17(9): 1727-1735.
Newman, L., Walker, M.T., Brown, R.L., Cronin, T.W., & Robinson, P.R. (2003)
Melanopsin forms a functional short-wavelength photopigment;
Biochemistry 42(44):12734-12738 .
Brown, R.L., Lynch, L. L., Haley, T.L., & Arsanjani, R. (2003)
Pseudechetoxin binds to the pore turret of cyclic nucleotide-gated ion
channels; J. Gen. Physiol. 122(6): 749-760.
Brown, R.L. & Robinson, P.R. (2004) Melanopsin – shedding light on the
elusive circadian photopigment; Chronobiology International 21(2):
189-204.
Warren, E.J., Allen, C.N., Brown, R.L., & Robinson, D.W. (2006) The
light-activated pathway in SCN-projecting retinal ganglion cells;
European J. Neurosci. 23: 2477-2487.
Jenkins, P., Hurd, T., Zhang, L., Brown, R.L., Margolis, B., Verhey, K., &
Martens, J.R. (2006) Ciliary targeting of olfactory CNG channels requires
the CNGB1b subunit and the kinesin motor protein, Kif17; Curr. Biol.
16(12):1211-6.
Perez-Leon, J. A., Warren, E.J., Allen, C.N., Robinson, D.W., & Brown, R.L.
(2006) Synaptic inputs to retinal ganglion cells that set the circadian
clock; European J. Neurosci. 24(4): 1117-23.
Brady, J.D., Rich, E., Martens, J.R., Karpen, J.W., Varnum, M.D., & Brown,
R.L. (2006) Interplay between PIP3 and calmodulin regulation of olfactory
CNG channels; Proc. Nat’l. Acad. Sci. USA 103(42): 15635-40.
Brown, R.L., Strassmaier, T., Brady, J.D., & Karpen, J.W. (2006)
Pharmacology of cyclic nucleotide-gated ion channels: emerging from the
darkness; Current Pharm. Design. 12 (28): 3571-3695.
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.
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