Multi-scale, numerical modeling of spatio-temporal signaling in cone phototransduction

PLoS One. 2019 Jul 25;14(7):e0219848. doi: 10.1371/journal.pone.0219848. eCollection 2019.

Abstract

Mammals have two types of photoreceptors, rods and cones. While rods are exceptionally sensitive and mediate vision at very low illumination levels, cones operate in daylight and are responsible for the bulk of visual perception in most diurnal animals, including humans. Yet the mechanisms of phototransduction in cones is understudied, largely due to unavailability of pure cone outer segment (COS) preparations. Here we present a novel mathematical model of cone phototransduction that explicitly takes into account complex cone geometry and its multiple physical scales, faithfully reproduces features of the cone response, and is orders of magnitude more efficient than the standard 3D diffusion model. This is accomplished through the mathematical techniques of homogenization and concentrated capacity. The homogenized model is then computationally implemented by finite element method. This homogenized model permits one to analyze the effects of COS geometry on visual transduction and lends itself to performing large numbers of numerical trials, as required for parameter analysis and the stochasticity of rod and cone signal transduction. Agreement between the nonhomogenized, (i.e., standard 3D), and homogenized diffusion models is reported along with their simulation times and memory costs. Virtual expression of rod biochemistry on cone morphology is also presented for understanding some of the characteristic differences between rods and cones. These simulations evidence that 3D cone morphology and ion channel localization contribute to biphasic flash response, i.e undershoot. The 3D nonhomogenized and homogenized models are contrasted with more traditional and coarser well-stirred and 1D longitudinal diffusion models. The latter are single-scale and do not explicitly account for the multi-scale geometry of the COS, unlike the 3D homogenized model. We show that simpler models exaggerate the magnitude of the current suppression, yield accelerated time to peak, and do not predict the local concentration of cGMP at the ionic channels.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Finite Element Analysis
  • Light Signal Transduction*
  • Models, Theoretical
  • Retinal Cone Photoreceptor Cells / metabolism*
  • Spatio-Temporal Analysis

Associated data

  • Dryad/10.5601/dryad.gr5768f

Grants and funding

The authors CK, GC, VVG, and ED are partially supported by National Science Foundation grant DMS 1812601. CK is supported at The Mathematical Biosciences Institute. MBI receives funding through the National Science Foundation Grant DMS 1440386. NSF had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.