Scientists uncover molecular mechanism that tunes eye light sensitivity

Weill Cornell Medicine investigators have determined the mechanism by which a molecule within cells can help tune the light sensitivity of the eyes. The study identified the molecule's binding site on a protein in retinal cells, which should enable the development of drugs that target this site to treat related eye diseases.

The study, published Sept. 3 in Nature Communications, examined the workings of the molecule known as PIP2 (PI(4,5)P2). This is a phospholipid found in the membranes of most human cells, and has a wide variety of signaling and regulatory functions. Prior research suggests that PIP2 can help tune the sensitivity of light-sensing "rod" cells in the retina by inhibiting the activation of a key ion channel called a CNG channel. But how PIP2 may do this has been unclear. PIP2's concentration in the membranes of rod cells appears to be very low, and it is hard to measure and even harder to manipulate experimentally. The researchers used model membranes containing CNG channels and well defined PIP2 concentrations, plus high-resolution imaging techniques, to determine precisely how and where PIP2 binds to CNG channels to inhibit their activity. The results also made clear that the very low concentrations of PIP2 seen in rod cells work efficiently enough to inhibit the channel and potentially exert a vision-regulating effect.

These findings establish a framework for understanding how lipids such as PIP2 regulate ion channel activity, and reveal the specific site where a drug could target CNG channels to inhibit their activity."

Dr. Crina Nimigean, study senior author, Distinguished Professor of Anesthesiology Research II and professor of biochemistry and biophysics in anesthesiology, Weill Cornell Medicine

Regulators of light sensitivity in the retina underlie the remarkable ability of animal vision to work across a very wide range of light levels—considerably wider, for example, than that of film or the semiconductor-based light sensors on modern digital cameras. PIP2's inhibition of CNG channels in rod cells may be part of that regulatory system to help maintain optimal vision in conditions where rod cells are particularly important, namely in low-light conditions and at the edges of the visual field.

"We think that PIP2's regulation of CNG channels is part of a natural process of tuning light sensitivity in these cells," said study first author Dr. Taehyun Park, a postdoctoral fellow in the Department of Anesthesiology.

Understanding how PIP2 works to inhibit CNG channels also has potential clinical importance. Some forms of retinal degeneration and vision loss are caused by defective CNG channels that end up killing rod cells. In principle, a drug targeting PIP2's binding site on CNG channels could repair the defective phenotype and ameliorate such conditions. But the structural specifics of that binding site and PIP2's inhibitory effect have been unclear.

The scientists crafted cell-membrane-like lipid structures with CNG channels and different concentrations of PIP2, and confirmed that PIP2 effectively keeps CNG channels closed even at very low concentrations. Cryogenic electron microscopy also revealed precise structural details of how PIP2 molecules bind to these channels and hold them in a closed state.

The results overall offer the first clear and convincing picture of how PIP2 regulates rod-cell CNG channels, the researchers said.

The Nimigean lab is now following up by studying lipid regulators that help tune vision by activating CNG channels instead of inhibiting them. Their model-membrane approach, which allows precise control of any lipid constituent, also should enable progress in many other research directions, Dr. Nimigean said.