Research in Dr. Pittler's laboratory focuses on the biochemistry and molecular biology of photoreceptor cells. Within these cells the initial events mediating vision occur. Light is absorbed in the photoreceptors by the receptor molecule, rhodopsin (R) which then activates another protein, transducin (T). Transducin activates a third protein, cGMP phosphodiesterase (PDE) that leads to the hydrolysis of cyclic guanosine monophosphate (cGMP). The drop in cGMP levels closes a cGMP-gated cation channel in the plasma membrane triggering the formation of an electrical impulse that is transmitted to the brain. Guanylate cyclase (GC) mediates the return to the dark state by replenishing the cGMP levels. Other ancillary proteins regulate the system to allow a response over 8 orders of magnitude of light intensity. The retina is comprised of several layers of cells; the ganglion cell layer (GCL) is oriented towards the center of the eye. These cells have long axons that traverse the retina and extend back to the brain. The inner plexiform layer (IPL) consists of synaptic connections between ganglion cells and inner retinal neurons. The inner nuclear layer consists of the nuclei of the inner retinal cells. The outer segment (OS), inner segment (IS) and outer nuclear layer (ONL) is comprised of the corresponding segments of photoreceptor cells. The phototransduction process that initiates vision is active in the photoreceptor outer segments. The current primary focus in my laboratory is on the biochemistry, cell biology and molecular biology of the cGMP-gated cation channel of the rod photoreceptor. This channel consists of two related subunits (alpha and beta) in a tetrameric complex consisting of 1 beta and 3 alpha subunits. The beta subunit appears to be a modulatory subunit of the activity that is observed with the alpha subunit alone. We are focusing on the beta subunit gene which is very complex encoding multiple transcripts that are likely to be initiated by multiple promoters. We have generated a knockout of the gene in mice and have found that the beta subunit is required for normal functional expression of the channel and that both the beta subunit and a related GARP protein expressed from the same gene are required for outer segment structural integrity. We are currently working on further characterization of the structural and functional roles of the beta subunit and GARP proteins.
A second focus of the laboratory is a translational approach to the treatment of a defined group of hereditary retinal disorders collectively known as retinitis pigmentosa (RP). Classic RP presents with night blindness, attenuated retinal vessels, bone-spicule like pigmentation, and narrowed visual fields. We are working with a new class of compounds that has been shown to promote read-through of premature stop codons. We are testing the potential to use this class of compounds as a novel molecular drug treatment to restore vision to the 5-15% subset of RP that is due to nonsense mutations.
Dr. Steven Pittler received his Ph.D. degree from Michigan State University in 1989. He completed his postdoctoral training at Baylor College of Medicine in 1991. In 1999, Dr. Pittler joined the UAB faculty as an Associate Professor in the Department of Physiological Optics.