A Model for Direction Sensing in Dictyostelium Discoideum: Ras Activity and Symmetry Breaking Driven by a Gbetagamma- Mediated, Galpha2-Ric8 -- Dependent Signal Transduction Network

TL;DR

This paper presents a new reaction-diffusion model for Ras activation in Dictyostelium discoideum, emphasizing Gbetagamma and Galpha2-Ric8 mediated signaling, which explains direction sensing and symmetry breaking in chemotaxis.

Contribution

It introduces a novel Ras activation model based on equal diffusion coefficients and local sequestration, differing from traditional LEGI models, highlighting Ric8's role in directional sensing.

Findings

Ric8-modulated G2 cycling explains Ras response dynamics

Model accounts for cellular memory and imperfect adaptation

Provides insights into symmetry breaking in chemotaxis

Abstract

Many eukaryotic cells, including Dictyostelium discoideum (Dicty), neutrophils and other cells of the immune system, can detect and reliably orient themselves in chemoattractant gradients. In Dicty, signal detection and transduction involves a G-protein-coupled receptor (GPCR) through which extracellular cAMP signals are transduced into Ras activation via an intermediate heterotrimeric G-protein (G2). Ras activation is the first polarized response to cAMP gradients in Dicty. Recent work has revealed mutiple new characteristics of Ras activation in Dicty, thereby providing new insights into direction sensing mechanisms and pointing to the need for new models of chemotaxis. Here we propose a novel reaction-diffusion model of Ras activation based on three major components: one involving the GPCR, one centered on G2, and one involving the monomeric G protein Ras. In contrast to existing local excitation, global inhibition (LEGI) models of direction sensing, in which a fast-responding but slowly-diffusing activator and a slow-acting rapidly diffusing inhibitor set up an internal gradient of activity, our model is based on equal diffusion coefficients for all cytosolic species, and the unbalanced local sequestration of some species leads to gradient sensing and amplification. We show that Ric8-modulated G2 cycling between the cytosol and membrane can account for many of the observed responses in Dicty. including imperfect adaptation, multiple phases of Ras activity in a cAMP gradient, rectified directional sensing, and cellular memory.