Cyclic GMP and calcium: The internal messengers of excitation and adaptation in vertebrate photoreceptors

The roles of cyclic GMP (cGMP) and calcium (Ca²⁺) in vertebrate rod phototransduction are reviewed, with the emphasis on developments since the discovery of the cGMP-activated conductance of the rod outer segment. The first hypothesis subjected to critical examination is that cGMP acts as the sole internal messenger of excitation. This hypothesis is evaluated with a formal, quantitative model of the biochemical actions of cGMP. Application of the model shows a remarkable agreement between independent electrophysiological and biochemical measurements of the resting dark amounts of (1) total cGMP (2) free cGMP (3) fraction of open cGMP-activated channels and (4) the rate of cGMP hydrolysis. The second hypothesis examined is that Ca²⁺ acts as an internal messenger in rod light adapatation. Recent electrophysiological evidence has shown minimization of the normal light-induced reduction of free Ca²⁺ prevents rods from exhibiting the change in sensitivity and speed characteristic of light adaptation. Physiological effects, formerly attributed to a role of calcium as an excitational messenger are shown to be consistent with a biochemical model in which Ca²⁺ serves as the cytoplasmic signal in a powerful feedback loop that acts to restore the concentration of cGMP both during and after exposure to light. Residual problems facing the "cGMP cascade theory of phototransduction" are reviewed. Issues are itemized that will have to be resolved quantitatively before it will be possible to develop a fully comprehensive theory of photoreceptor excitation, restoration and adaptation combining the roles of Ca²⁺ and cGMP.