Analysis of ERG a-wave amplification and kinetics in terms of the G- protein cascade of phototransduction

Purpose. To test rigorously the hypothesis that the a-wave of the electroretinogram (ERG) is proportional to the rod photocurrent by examining the applicability to a-waves of a recent model of the activation steps in the G-protein cascade of phototransduction. Methods. ERGs were recorded in response to flashes of graded intensity, from six dark-adapted normal subjects and from two patients, one with retinitis pigmentosa (RP) and one with cone retinal dystrophy with rod involvement (CRD). The a-wave portions of the responses were analyzed with a model of the activation steps of the G- protein cascade. The model is characterized by a parameter, A, the amplification constant, with units of s^-2 (per photoisomerization), which may be expressed as the product of physical and biochemical parameters of the transduction cascade. Results. Each a-wave family was well described by the model. For the six normal subjects, we obtained A ≃ 7 s^-2, about 100-fold greater than in isolated amphibian rods at 22°C, but close to the value for isolated primate rods. For the patient with RP, the maximum a-wave amplitude (a(max)) was considerably reduced, but the amplification constant was normal (A = 7.5 s^-2). In contrast, the patient with CRD had a nearly normal a(max) but had an amplification constant about sixfold lower than normal (A = 1.1 s^-2). Conclusions. The authors conclude that the a-wave is a direct reflection of the rod photocurrent and that the rising phase kinetics are accurately described by a simple model of the G-protein cascade. They show that the small volume of the human rod outer segment is crucial to the achievement of high amplification, and they show how their observations constrain the possible pathologies of phototransduction in patients with retinal disease.