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Vision

The need for speed

Neurons in the retina turn on and off rapidly in response to light. With the discovery of mutations in human genes that mediate this quick turn-off, we have the first picture of its importance in visual perception.

Imagine walking out of a dark theatre into a bright and sunny Sunday afternoon. You are momentarily blinded, but your eyes rapidly adjust to the change and you continue on your way. For some people with a rare visual defect, however, this momentary blindness can last for up to ten seconds. A similar, but potentially more dangerous, prolonged blindness occurs when these individuals drive from daylight into a darkened tunnel. Moreover, people with this problem also suffer from difficulties in seeing certain moving objects (such as balls thrown during a sporting event). On page 75 of this issue, Nishiguchi et al.1 describe a genetic cause of this condition. In so doing, they reveal that visual perception requires rapid deactivation of the light-stimulated responses shown by neurons in the eye.

Light streaming into the eye is detected by specialized neurons (photoreceptors) in the retina. In response to light, a coordinated series of molecular events — the so-called phototransduction cascade — is triggered in these cells2 (Fig. 1). Photons excite pigment-containing proteins called rhodopsins, which then switch on the protein transducin by loading it with the small molecule guanosine triphosphate (GTP). When bound to GTP, transducin turns on a phosphodiesterase, an enzyme that breaks down cyclic guanosine monophosphate (cGMP — another small molecule). High concentrations of cGMP open specialized ion channels in the outer cell membrane. Thus, by reducing the concentration of cGMP, light changes the flow of ions across the membrane of photoreceptive neurons, producing an electrical signal that is necessary for communicating with the brain.

Figure 1: Phototransduction in photoreceptor cells.
figure1

In the rod class of photoreceptors, the pigment-containing protein rhodopsin absorbs light (a) and activates transducin (b) by causing it to release GDP and bind GTP. GTP-bound transducin binds to and activates a phosphodiesterase (PDE), which converts cGMP to GMP (c). The concentration of cGMP decreases below what is required to open cGMP-gated ion channels, reducing the flow of ions across the cellular membrane. RGS9 bound to R9AP turns off the light-induced response by accelerating the rate of GTP hydrolysis by transducin, releasing phosphate, P (d). Other proteins that regulate the phototransduction cascade have been omitted for clarity. Nishiguchi et al.1 have identified several people with mutations in RGS9 or R9AP. These patients show slow photoreceptor deactivation and have difficulty in adjusting to changes in light levels, as well as in seeing low-contrast, moving objects.

Once this light-activated switch is on, how do cells turn it off? One mechanism is to limit the amount of time that GTP-bound transducin can keep the phosphodiesterase enzyme active. Transducin can accomplish this task itself by converting — hydrolysing — its bound GTP molecule into guanosine diphosphate, GDP. (This conversion from GTP to GDP is a commonly used molecular 'switch' in a variety of cellular signalling pathways.) Because transducin bound to GDP has a low affinity for phosphodiesterase, it releases the enzyme in an inactive form, allowing cGMP levels to rise again and return the flow of ions across the cell membrane to the 'dark' state. In this molecular cascade, then, the conversion of GTP to GDP by transducin is the rate-limiting step that defines the amount of time for which a photoreceptor responds to a light pulse.

But this presents a problem. Photoreceptor cells can turn off in less than a second in response to a brief flash of light2. In contrast, the hydrolysis of GTP by transducin requires tens of seconds to complete, making it difficult to understand how such a mechanism could account for the rapid turn-off of photoreceptor cells. To get around this problem, photoreceptor cells possess a protein called regulator of G-protein signalling 9 (RGS9) that accelerates transducin's ability to hydrolyse GTP3. Indeed, mice that lack the RGS9 gene exhibit slow photoreceptor deactivation4.

Building on these studies of mice, Nishiguchi et al.1 now show that disruption of this accelerator mechanism is the likely cause of a 'slow photoresponse recovery' condition previously described5 in several humans. The authors started by analysing the DNA of five unrelated people with the condition, and found that four of them had mutations in both copies of their RGS9 gene, producing a protein that is a poor accelerator of GTP hydrolysis. In the fifth patient, the RGS9 gene was normal. Instead, this person had a mutation that inactivates the R9AP gene, which encodes a retinal protein that anchors RGS9 to membranes6.

The identification of these mutations also provided an opportunity to study their effects on visual perception — something that, for obvious reasons, could not be studied in mice. The visual abnormalities of these patients were striking: all reported difficulties in adjusting to changes in light intensity (such as when walking out of that dark theatre). Measurements of the retinal activity in these individuals confirmed that adaptation to changes in dim or bright light, or recovery from a bright flash of light, was much slower than normal. Some patients reported that they could not participate in sport because they could not see a moving ball. In agreement with this complaint, the patient who had a mutation in R9AP also had greatly impaired visual acuity (20/200) for moving, low-contrast objects, although visual acuity was nearly normal in standard tests using high-contrast objects. The findings indicate that adaptation to changing light conditions, visual acuity and contrast detection require that photoreceptors be able to deactivate rapidly. Contrast perception is likely to be impaired because the retinal cells that relay signals to the brain respond most strongly to rapid changes in input from photoreceptor cells. Given these findings, Nishiguchi et al.1 propose calling this condition bradyopsia ('slow vision').

RGS9 is one of nearly 30 such RGS proteins, which regulate signalling by hundreds of receptors coupled to transducin-like G proteins in cell networks of the nervous, cardiovascular, sensory and immune systems7. In addition to its function in the retina, RGS9 is highly expressed in the rodent brain and is involved in controlling the rewarding effects of dopamine and the pain-killing effects of morphine8,9. Human RGS4 is also expressed in the brain and has been linked to schizophrenia10, whereas rodent RGS2 is widely expressed and regulates immune function, aggressive behaviour and blood pressure11,12. Nishiguchi and colleagues' study1, however, represents the first description of a human condition that is linked to reduced RGS function. It seems likely that more examples of human disorders that are caused by impaired RGS function will be discovered as our understanding of these signalling molecules increases.

References

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