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Peter Detwiler
Professor
Ph.D. Pharmacology
Georgetown University, 1970
Office phone: (206) 543-0957
detwiler@uw.edu

 

CELLULAR AND MOLECULAR PROPERTIES OF SENSORY TRANSDUCERS

In order for a few trillion cells to get together and build a free-roaming, self-perpetuating, fully imagining, multicellular biomachine such as ourselves they have to be able to communicate. They have to be able to see, hear, smell, touch and taste their neighbors. If they can't, the machine falls apart and becomes diseased.

I am interested in how cells detect and respond to signals in their external environment. Our lab is studying how a prototypic signal transduction pathway works by examining the molecular mechanisms by which retinal rod photoreceptor cells detect and respond to light. We study rod phototransduction for three main reasons. First, light is an ideal stimulus because it can be defined precisely, measured accurately and easily turned on and off. Second, rods are enormously sensitive to light; they can signal the absorption of a single photon. Third, photoreceptors are made up of three morphologically and functionally distinct regions that perform separate chores. The outer segment is the region that transduces light. We have developed methods to detach it from the rest of the photoreceptor and resuscutate the phototransduction process using intracellular dialysis via whole-cell voltage clamp. Current flows into the outer segment through cyclic nucleotide gated channels in the surface membrane that are closed b y light. We study the molecular events that couple light to channel closure by using dialysis to alter the biochemical composition of the cytoplasm with the aim of altering identified steps in the transduction cascade.

We have learned that phototransduction involves reciprocal changes in two intracellular second messengers, cGMP and Ca. By combining electrical recording techniques with simultaneous optical measurements we have been able to monitor the light-evoked changes in cGMP and Ca. These two messengers are tightly interconnected and play an important role in regulating sensitivity, kinetics and adaptational state of the receptor. Since vertebrate phototransduction is the most throughly studied example of a G protein-coupled signal transduction pathway we expect that what we learn about how photoreceptors work will be generally relevant to understanding other kinds of less well studied G protein-coupled pathways.