department of pharmacology

Krzysztof Palczewski, Ph.D.

Krzysztof Palczewski

John H. Hord Professor and Chair
Department of Pharmacology

Senior Fellow of the American Asthma Foundation

School of Medicine, W319
2109 Adelbert Rd.
Case Western Reserve University

Mailing Address:
10900 Euclid Ave.
Cleveland, Ohio 44106-4965

Publications
Academic Experience
Laboratory

 

Research

The light-sensing apparatus of the eye is found within the rods and cones—two types of specialized cells located in the posterior of the retina. Of the two types of receptors, rod cells exhibit greater light sensitivity (lower threshold) and a slower reaction time. Cone cells, on the other hand, respond rapidly, and provide greater discrimination of temporal, spatial, and spectral detail. The light signal captured by photoreceptor cells triggers a cascade of chemical reactions, called phototransduction, which ultimately generates a neuronal signal.


Rhodopsin Dimer

Like the rod cell, cone cell activation involves the photoisomerization of the 11-cis-retinal chromophore bound to an opsin-like transmembrane protein. In the case of the cone cell, however, there are three variants of the transmembrane protein. When bound to the chromophore, each of the resulting visual receptor pigments exhibit a characteristic red, blue, or green absorption maxima which leads ultimately to color vision. Recent work indicates that the differences in absorption maxima are a function of differences in amino acid sequences within each pigment. Similar analyses of structure, reactivity and function will have to be performed for all the critical receptors, catalysts (G-proteins, kinases, phosphoesterases, retinal dehydrogenases), and reaction terminators (arrestins, recoverins, guanylate cyclase activating proteins) within the cone cells phototransduction cycle.


GCAP

Light-triggered events initiated in rod and cone outer segments were the subject of numerous investigations during the last two decades, most notably using molecular approaches and electrophysiological measurements of the isolated retina or photoreceptor cells. The light events are intimately intertwined with the regeneration reactions that involve two cell systems. Every photon of light that triggers photoisomerization is counterbalanced by regeneration of rhodopsin with newly synthesized 11-cis-retinal. Contributions from numerous investigators have provided substantial advances in our fundamental knowledge of phototransduction and the regeneration of rhodopsin. These have included the identification of phototransduction and retinoid processing enzymes, cation channels, and retinoid-binding proteins in the retina-RPE system, and determination of the mechanisms of action of these proteins. Furthermore, within the past decade there has been substantial new information regarding the links between specific retinal diseases and identified abnormalities of the retinoid cycle.

Many unresolved issues relevant to phototransduction, light- and dark-adaptation, and the chemical processing of retinoid cycle intermediates remain unanswered, including the enzymology of the retinoid cycle, the mechanisms by which these intermediates diffuse within and between the photoreceptors and the RPE, and the dependence of phototransduction reactions on the operation of the cycle. These important questions pose exciting challenges for future research on the visual cycle, and are certain to continue as the subject of intense interest for Professor Palczewski’s laboratory.

The goal of Professor Palczewski’s laboratory is to:

  • Understand the biochemical basis underlying the mechanism of rhodopsin inactivation and restoration of the cGMP level.
  • Delineate the biochemical basis underpinning the similarities and differences between rod and cone cell phototransduction.
  • Understand the enzymology of the isomerization of all-trans-retinol to 11-cis-retinol in the retina.

Knowledge about phototransduction in the retina, a system with great experimental advantages, will improve further understanding of similar events in hormonal signaling, cellular communication and immune regulation, and provide baseline information for further studies of retinal disease processes.