Unified mechanism for relay and oscillation of cyclic AMP in Dictyostelium discoideum.

Abstract

A modified version of an allosteric model for adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] previously analyzed for sustained oscillations of adenosine 3':5'-cyclic monophosphate (cAMP) in Dictyostelium discoideum [Goldbeter, A. (1975) The cellular slime mold Dictyostelium discoideum is a major model for the study of development (1, 2). When deprived of nutrients, amoebae of this species aggregate around centers by a chemotactic response to adenosine 3':5'-cyclic monophosphate (cAMP), and further develop into multicellular fruiting bodies (3). The process of aggregation has a periodicity of several minutes. Successive "steps" of inward amoeboid movement appear to propagate outward from the center toward the periphery of the aggregation territory. It has long been suggested that aggregation centers autonomously release the attractant in periodic fashion. The other cells respond to attractant stimulation by moving towards its source and by relaying the signal (4-8). In addition to their role as chemotactic signals, periodic pulses of cAMP stimulate amoeboid differentiation (9, 10).Both the relay (11, 12) and the autonomous oscillation (13, 14) of cAMP have been demonstrated experimentally in suspensions of D. discoideum cells. We show here that oscillation and relay can be explained by a unified model based on regulatory mechanisms reported in the literature, the two different qualitative behaviors corresponding to two different parameter regimes. Our work can be regarded as extending Goldbeter's demonstration (15) that oscillation can be generated by the intracellular regulation (16) of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1]. Here, we consider a compartmental model in which control of intracellular cAMP synthesis by external cAMP is analyzed explicitly.The unified mechanism for relay and oscillation of cAMP suggests an explanation for the emergence of aggregation centers and for a temporal sequence of developmental events observed during interphase in D. discoideum. RESULTSIn an attempt to capture the essential biochemical mechanisms responsible for oscillation and relay, let us consider the activating effect of extracellular cAMP on adenylate cyclase (17). This activation follows the binding of cAMP to a receptor that might be specific for relay (18). The simplest assumption one can make is that the cAMP receptor on the cell surface is a regulatory part of adenylate cyclase; such an assumption is consistent with the finding that the catalytic site of this membrane-bound enzyme faces the interior of the cell (19). We thus consider the following three concentration variables in a basic compartmental model (see Fig. 1):a, intracellular ATP; fB intracellular cAMP; -y, extracellular cAMP.[1] Here the actual concentrations are normalized by dividing them respectively by Ks, Kp, and Kp, where Ks and Kp are the Michaelis constant of adenylate cyclase for ATP and the dissociation constant of complexes formed by the enzyme with cAMP at the regulatory (receptor) ...

A Model for a Network of Phosphorylation–dephosphorylation Cycles Displaying the Dynamics of Dominoes and Clocks

“…For the sake of clarity, the values of X and X in (d) have been multiplied by 10 and 10 , respectively. Parameter values for the cAMP oscillations generated by eqns (3) are "1.2, v"1.2, k"k R "0.4,¸"10 , q"100, h"10 (see Goldbeter & Segel, 1977;. Other parameter values are: (b) < + "0.5, The oscillations of intracellular cAMP (b) produced by this model are shown in Fig.…”

“…model previously proposed for pulsatile cAMP signaling in Dictyostelium discoideum amoebae (Goldbeter & Segel, 1977;. Other models for cAMP oscillations could be used (e.g.…”

“…The model for cAMP oscillations in D. discoideum is governed by the three kinetic equations (3) which describe the time evolution of the concentrations of intracellular ATP, intracellular cAMP, and extracellular cAMP; these three variables are denoted by a, b and c, respectively [see Goldbeter &Segel (1977), and, for further details on these equations and on the signi"cance of the parameters]:…”

Excitability in the adenylate cyclase reaction in Dictyostelium discoideum

“…Under relay conditions, a suprathreshold signal of extracellular cAMP elicits a pulsatory synthesis of intracellular cAMP of much larger magnitude. We analyze here this amplification process in a model [10] proposed for relay and oscillation of cAMP in D. discoideum, and show that it represents an excitable response of adenylate cyclase.…”

Computational modelling suggests dynamic interactions between Ca2+, IP3 and G protein-coupled modules are key to robust Dictyostelium aggregation

“…11,12 The rule-based modelling of Dictyostelium movement was further developed into computer models of Dictyostelium aggregation in refs. 13-15. Other early models, which were developed before the role of G proteins was discovered, focussed on oscillations in ATP and cAMP concentrations 16,17 or on interactions between Ca 2+ and camp. 18 A third set of models employed simplified reaction-diffusion equations.…”