Tracking Electrical Signals from Eye to Brain

When a photon of light hits the retina, the signal ultimately transmitted to the brain is electrical. At the molecular level, the way the electrical signal is turned on and off is mechanical. In retinal cell membrane, the flow of electrically charged atomic particles depends upon the shape of certain protein molecules. Their structure incorporates a hole that opens or closes like a pore on the skin.

“These molecules do something remarkable and elaborate,” said Dr. William N. Zagotta, professor of physiology and biophysics. “We’re interested in how the molecular mechanics works: how the channels open and close their pores.”

The protein molecules -- called ion channels, because they form a gated channel for the flow of charged particles -- are crucial components of cell-signaling pathways for the senses of sight, smell, and taste. Furthermore, the underlying mechanism is fundamental to brain signaling. All cells in the body have these electrical gateways in their membranes. Brain cells are particularly rich in them.

“Ion channels are the fundamental molecules that produce electrical activity in the brain,” said Zagotta. “This is the elementary mechanism by which the brain works.”

In 2001 and 2002, Zagotta produced important research results on ion channel kinetics at two key sites in the molecular structure: firstly, at the pore; secondly, at a site where another molecule binds and effects the opening of the pore.

Zagotta’s lab studies ion channels both in the retina and in olfactory tissue. The latter produce an electrical signal when scent molecules bind receptors in the nose.

Signaling is intricate. The retinal ion channels, for example, are not directly sensitive to light. Light sensitive proteins in the retinal cells initiate a cascade of chemical signals. This cascade culminates in lowering the concentration of a small organic molecule, a cyclic nucleotide called cGMP. The ion channel pore is open when cGMP is bound to it. When light hits the photoreceptor neurons, the level of cGMP drops, and the pore closes in response. The blockage of ions flowing into the cell changes the voltage and generates an electrical signal. Although ion channels are too small to see, even under a microscope, experiments can record ions flowing through a single pore.

In a 2001 paper in Nature, Zagotta described the movement of the molecular structure as the retinal receptor ion channel pore opens and closes. In 2002, during a sabbatical in the lab of Dr. Eric Gouaux, professor of biochemistry and molecular biophysics at Columbia University, breakthrough work using X-ray crystallography confirmed the structure of the binding site.

For his outstanding research, Zagotta received the Biophysical Society’s 2002 Michael and Kate Barany Award for Young Investigators.