two patients with retinal disease (12). For a patient with retinal dystrophy, the magnitude of the circulating current was normal but the amplification constant of phototransduction was significantly reduced, while for a patient with sector retinitis pigmentosa the amplification constant was normal but the magnitude of the circulating current was reduced.

Comparison of Estimates of νRE. The rate νRE of activation of E* in response to a single R* may be estimated by substituting the measured amplification constant into Eq. 5, provided that the values of the constants are known. For amphibian rods at room temperature, recent estimates of the physical parameters are kcat = 4400 s−1 and Km = 95 µM (14), n = 2 (15), Vcyto = 1 pl, and BP = 1–2 (7), so that the term in square brackets in Eq. 5 becomes 3.8−7.6 × 10−5 s−1νRE. Adopting this factor, the mean experimental value of A = 0.076 s−2 yields a PDE activation rate of νRE = 1000–2000 E* s−1 per R* for salamander rods at 22°C.

This estimate for the rate of E* activation is within a factor of 2 of previous estimates of the rate of G-protein activation from light-scattering methods, which have given 800–1100 G* s−1 per R* at room temperature (16,17). The value is, however, considerably higher than earlier estimates obtained from PDE assays (based on the release of protons during cGMP hydrolysis), which yielded values in the region of 100–200 E* s−1 per R* at room temperature, but it seems likely that those in vitro measurements significantly underestimated the true rate. However, irrespective of the precise rate of protein activation, the form of the onset phase of the electrical response is predicted accurately by the model based on twodimensional lateral diffusion of proteins at the membrane.

The Future. Now that activation of the electrical response can be described quantitatively, a major challenge for the future will be to provide a comprehensive description of the shutoff reactions. Once the inactivation steps can be described quantitatively at a molecular level, it should be straightforward to incorporate them into the stochastic model WALK. This will enable us to paint a complete picture of the photoreceptor 's light response that includes not only the onset phase but also its recovery and the important phenomenon of light adaptation. When a comparable level of quantitative information is available for other G-protein cascades (such as the β-adrenergic and olfactory receptor mechanisms), it should similarly be possible to describe the gain and kinetics of their responses to stimulation.

I gratefully acknowledge the continued encouragement of Professor E. N. Pugh, Jr. This work was supported by grants from the Wellcome Trust (034792), the European Commission (SSS 6961), and the Human Frontiers Science Program (RG-62/94).

1. Stryer, L. ( 1991) J. Biol. Chem. 266, 10711–10714.

2. Hargrave, P. A., Hofmann, K. P. & Kaupp, U. B., eds. ( 1991) Signal Transduction in Photoreceptor Cells (Springer, Berlin).

3. Hofmann, K. P. & Heck, M. ( 1995) in Biomembranes II, ed. Lee, A. G. (JAI Press, Greenwich, CT), in press.

4. Pugh, E. N., Jr., & Lamb, T. D. ( 1993) Biochim. Biophys. Acta 1141, 111–149.

5. Baylor, D. A. ( 1996) Proc. Natl. Acad. Sci. USA 93, 560–565.

6. Yau, K.-W. & Baylor, D. A. ( 1989) Annu. Rev. Neurosci. 12, 289–327.

7. Lamb, T. D. & Pugh, E. N., Jr. ( 1992) J. Physiol. 449, 719–757.

8. Lamb, T. D. ( 1994) Biophys. J. 67, 1439–1454.

9. Jaeger, J. C. ( 1942) Proc. R. Soc. Edinburgh 61A, 223–228.

10. Pepperberg, D. R., Cornwall, M. C., Kahlert, M., Hofmann, K. P., Jin, J., Jones, G. J. & Ripps, H. ( 1992) Visual Neurosci. 8, 9–18.

11. Torre, V., Matthews, H. R. & Lamb, T. D. ( 1986) Proc. Natl. Acad. Sci. USA 83, 7109–7113.

12. Breton, M. E., Schueller, A. W., Lamb, T. D. & Pugh, E. N., Jr. ( 1994) Invest. Ophthalmol Visual Sci. 35, 295–309.

13. Cideciyan, A. & Jacobson, S. G. ( 1996) Vision Res., in press.

14. Dumke, C. L., Arshavsky, V. Y., Calvert, P. D., Bownds, M. D. & Pugh, E. N., Jr. ( 1994) J. Gen. Physiol. 103, 1071–1098.

15. Koutalos, Y., Nakatani, K. & Yau, K. W. ( 1995) Biophys. J. 68, 373–382.

16. Vuong, T. M., Chabre, M. & Stryer, L. ( 1984) Nature (London) 311, 659–661.

17. Hofmann, K. P. & Kahlert, M. ( 1992) in Signal Transduction in Photoreceptor Cells, eds. Hargrave, P. A., Hofmann, K. P. & Kaupp, U. B. (Springer, Berlin).



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