Abstract
Purpose: :
The mGluR6/TRPM1 transduction cascade mediates the light responses of ON bipolar cells. It is unusual among G-protein coupled receptors because ligand-binding rapidly modulates channel opening and closure. Its molecular constituents have been partially identified and their properties are partially understood. A molecular model of the mGluR6/TRPM1 transduction cascade based on a similar system, the mammalian phototransduction cascade, might account for known physiology and contribute to future experimental design.
Methods: :
We created a 3D model of the synaptic cleft and postsynaptic transduction cascade using the molecular simulation software mcell. Molecular properties (diffusion constants, EC50s, concentrations, etc.) and structural properties (cleft depth, dendritic tip size, etc.) were estimated from the literature. Unidentified molecules were created to serve putative functions: an effecter molecule activated by Gαo, a transmitter molecule to close TRPM1 channels, and a feedback molecule to accelerate channel closure following channel activation.
Results: :
We compared model output to light responses from mouse rod bipolar cells. The fast kinetics of the synaptic response require (1) fast unbinding of glutamate from mGluR6, and (2) small fluctuations in the number of open TRPM1 channels for large fluctuations of glutamate concentration in darkness. Our model reproduced general features of the system, such as the magnitude and kinetics of the light response, saturation of the postsynaptic transduction cascade in darkness, and the effects of the high-affinity mGluR6 agonist APB.
Conclusions: :
Currently, successful models of photoreceptor function rely more on biophysics than pure statistical inference, and we expect this will be true for the mGluR6/TRPM1 transduction cascade. Our model explains how fluctuations in glutamate concentration in darkness can be filtered out as noise, while changes caused by light can be signaled reliably. Because its glutamate binding must be robust in darkness and its unbinding must be fast in light, the mGluR6 receptor must have high affinity and must be close enough to a presynaptic ribbon that the mGluR6 cascade saturates. This probably explains why ON bipolar cells make invaginating contacts, rather than adopting the strategy of most OFF bipolar cells whereby signal-to-noise ratio is improved by sampling release from multiple ribbons at basal contacts.
Keywords: bipolar cells • synapse • electrophysiology: non-clinical