Tuning Outer Segment Ca2+Homeostasis to Phototransduction in Rods and Cones

Abstract

Cone photoreceptors respond to light with less sensitivity, faster kinetics and adapt over a much wider range of intensities than do rods. These differences can be explained, in part, by the quantitative differences in the molecular processes that regulate the cytoplasmic free Ca2+concentration in the outer segment of both receptor types. Ca2+concentration is regulated through the kinetic balance between the ions’ influx and efflux and the action of intracellular buffers. Influx is passive and mediated by the cyclic-GMP gated ion channels. In cones, Ca2+ions carry about 35% of the ionic current flowing through the channels in darkness. In rods, in contrast, this fraction is about 20%. We present a kinetic rate model of the ion channels that helps explain the differences in their Ca2+fractional flux. In cones, but not in rods, the cGMP-sensitivity of the cyclic GMP-gated ion channels changes with Ca2+at the concentrations expected in dark-adapted photoreceptors. Ca2+efflux is active and mediated by a Na+and K+dependent exchanger. The rate of Ca2+clearance mediated by the exchanger in cones, regardless of the absolute size of their outer segment is of the order of tens of milliseconds. In rod outer segments, and again independently of their size, Ca2+clearance rate is of the order of hundreds of milliseconds to seconds. We investigate the functional consequences of these differences in Ca2+homeostasis using computational models of the phototransduction signal in rods and cones. Consistent with experimental observation, differences in Ca2+homeostasis can make the cone’s flash response faster and less sensitive to light than that of rods. In the simulations, however, changing Ca2+homeostasis is not sufficient to recreate authentic cone responses. Accelerating the rate of inactivation (but NOT activation) of the enzymes of the transduction cascade, in addition, to changes in Ca2+homeostasis are needed to explain the differences between rod and cone photosignals.