Facilitative glucose transporter Glut1 is actively excluded from rod outer segments.

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2010-11-01

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Abstract

Photoreceptors are among the most metabolically active cells in the body, relying on both oxidative phosphorylation and glycolysis to satisfy their high energy needs. Local glycolysis is thought to be particularly crucial in supporting the function of the photoreceptor's light-sensitive outer segment compartment, which is devoid of mitochondria. Accordingly, it has been commonly accepted that the facilitative glucose transporter Glut1 responsible for glucose entry into photoreceptors is localized in part to the outer segment plasma membrane. However, we now demonstrate that Glut1 is entirely absent from the rod outer segment and is actively excluded from this compartment by targeting information present in its cytosolic C-terminal tail. Our data indicate that glucose metabolized in the outer segment must first enter through other parts of the photoreceptor cell. Consequently, the entire energy supply of the outer segment is dependent on diffusion of energy-rich substrates through the thin connecting cilium that links this compartment to the rest of the cell.

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10.1242/jcs.072389

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Gospe, Sidney M, Sheila A Baker and Vadim Y Arshavsky (2010). Facilitative glucose transporter Glut1 is actively excluded from rod outer segments. J Cell Sci, 123(Pt 21). pp. 3639–3644. 10.1242/jcs.072389 Retrieved from https://hdl.handle.net/10161/4190.

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Scholars@Duke

Gospe

Sidney Maloch Gospe

Assistant Professor of Ophthalmology

Dr. Gospe joined Duke Ophthalmology on August 1, 2017 following his neuro-ophthalmology fellowship training at Duke. His research interests center on developing novel genetic mouse models of severe mitochondrial dysfunction in retinal ganglion cells (RGCs) and other retinal neurons in order to recapitulate the RGC degeneration seen in human optic neuropathies and the poorly understood pigmentary retinopathy that may accompany these diseases.

Mitochondria are the powerhouse of our cells, efficiently generating energy through oxidative metabolism. When mitochondria function improperly, cells are deprived of needed energy and are subjected to the adverse effects of reactive oxygen species. Mitochondrial dysfunction is an important cause of vision loss and is believed to play a mechanistic role in a number of optic neuropathies, most notably in primary mitochondrial optic neuropathies like Leber hereditary optic neuropathy and dominant optic atrophy, but also secondarily in more common diseases like optic neuritis, ischemic optic neuropathy, and glaucoma. Currently there are no pharmacotherapies for mitochondrial optic neuropathies that are of more than marginal clinical benefit to affected patients.

Dr. Gospe employs biochemical, histologic, and electrophysiological approaches to characterize the metabolic perturbations and aberrant signaling pathways leading to degeneration of retinal neurons in the face of reduced oxidative metabolism. The mutant mouse lines he is developing may serve as useful preclinical models to identify and validate therapeutic targets for future human trials. Ultimately, the hope is that strategies to modulate mitochondrial physiology may be neuroprotective not only in primary mitochondrial optic neuropathies but also in other optic neuropathies causing significant visual morbidity in patients.

Arshavsky

Vadim Y Arshavsky

Helena Rubinstein Foundation Distinguished Professor of Ophthalmology

The Biology and Pathophysiology of Vertebrate Photoreceptor Cells

Research conducted in our laboratory is dedicated to understanding how vision is performed on the molecular level. Most of our work is centered on vertebrate photoreceptor cells, which are sensory neurons responsible for light detection in the eye. Photoreceptors capture photons, produce an electrical signal, and transmit this information to the secondary neurons in the retina, and ultimately to the brain, through modulation of their synaptic release. 

The main experimental direction of our laboratory is to elucidate the cellular processes responsible for building the light-sensitive organelle of photoreceptor cells, called the outer segment, and for populating this organelle with proteins supporting its structure and conducting visual signaling. Of particular interest is the mechanism by which outer segments form their “disc” membrane stacks providing vast membrane surfaces for efficient photon capture. Outer segment membranes are continuously renewed throughout the lifetime of a photoreceptor, with new discs added to the outer segment base and old discs phagocytosed at the tip by the retinal pigment epithelium. As a result, the entire mammalian outer segment is replaced with new discs over the course of 8-10 days. One of the central goals of our current studies is to elucidate the signaling pathway that acts as a “control center” to initiate the formation of each new disc with the strikingly regular frequency of approximately 80 times per day. 

Our second major research direction explores a connection between understanding the basic function of rods and cones and practical, translational ideas aiming to ameliorate retinal degeneration caused by mutations in critical photoreceptor-specific proteins. Several years ago, we found that photoreceptors bearing a broad spectrum of disease-associated mutations suffer from a common cellular stress factor, proteasomal overload, i.e. insufficient ability of the ubiquitin-proteasome system to process misfolded and/or mislocalized proteins produced in these cells. Our more recent data demonstrate that the enhancement of protein degradation machinery in these cells causes a remarkable delay in the progression of photoreceptor degeneration. We continue investigating photoreceptor proteostasis in further mechanistic depth and seek optimal strategies to employ proteasomal activation as a means to ameliorate or cure inherited blindness. 

During our studies, we explore high-end applications of mass spectrometry-based proteomics and were the first laboratory adopting several advanced proteomic approaches to vision research. Of particular significance are the applications of so-called “label-free” quantitative proteomics for simultaneous elucidation of multiple protein distributions among different compartments of the photoreceptor cells and for identification of unique protein components of various photoreceptor membranes. Using label-free proteomics, we demonstrated that a small protein PRCD (progressive rod and cone degeneration) is a unique component of photoreceptor discs and subsequently identified several novel unique components of the plasma membrane enclosing the rod outer segment. Most recently, we adopted a highly efficient and accurate methodology for simultaneous absolute quantification of several dozen proteins, termed MS Western. This method allowed us to determine the precise molar ratio amongst all major functional and structural proteins residing in the light-sensitive outer segments of photoreceptor cells.


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