Fig. 4. Model describing accelerated signalling at the leading edge. (A) In resting cells, we found two receptor populations: immobile and mobile receptors. A fraction of the immobile receptors is coupled to G2^GDP/Gβ ,which, in turn, is coupled to protein-protein networks and/or the cytoskeleton which inhibits diffusion (1). This fraction of immobile receptors becomes mobile by uncoupling of G2^GTP upon cAMP activation. Free G2^GTP and free Gβ subunits activate intracellular signalling (2). The mobile receptors have the ability to further activate other G2^GDP/Gβ complexes in a diffusion-limited process (3). In a final step, re-association of the receptor with G2^GDP/Gβ and corresponding loss of cAMP immobilizes the receptor again (4). (B) An ellipsoidal cell is exposed to a gradient of 0.4nM/µm cAMP. The concentration at the leading edge is 66nM and that at the trailing edge 58nM. The density of active cAR1 receptor (cAR1^*) is plotted versus the position along the cell membrane. At the leading edge the density of active cAR1 is higher by a factor of 1.05 when compared with the density at the trailing edge (6.1 molecules/µm² versus 5.8 molecules/µm²) following the cAMP gradient. The density of activated Gβ at the leading edge was 73.0 molecules/µm², whereas that at the trailing edge was 71.4 molecules/µm². Hence, diffusion leads to a linear amplification of the gradient by a factor of 5.