cAMP-cGMP Chemotactic Interaction in D. discoideum
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cAMP-cGMP Chemotactic Interaction in D. discoideum

During random locomotion, human neutrophils and D. discoideum (Dictyostelium discoideum) amoebae repeatedly extend and retract cytoplasmic processes. Some types of cell are highly motile. They can sense the presence of extracellular signals and guide their movement in the direction of the concentration gradient of these signals (Ref.1). This process, called Chemotaxis, has a role in diverse functions such as the sourcing of nutrients by prokaryotes, the formation of multicellular structures in Protozoa, the tracking of bacterial infections by neutrophils, and the organization of the embryo in Metazoa. Chemotaxis is essential for survival, if cells fail to reach their proper destinations they die, or the organism dies, so it is expected that the mechanisms for processing Chemotactic signals have been optimized during evolution. In D. discoideum, Chemotaxis is comprised of three interrelated phenomena: the formation of periodic self-organizing pseudopodia, polarization and directional sensing. The social amoebae D. discoideum has proven indispensable to elucidate signaling events that regulate Chemotaxis and cAMP (Cyclic Adenosine 3,5-Monophosphate)-induced Chemotactic signaling has been extensively studied (Ref.2 & 3).

Early in development, cells are able to create new pseudopods at the sides and back upon a shift in the gradient, whereas more developed cells become relatively insensitive at the back. Some of the proteins critical for developing this polarity include those regulating PIP3 (Phosphatidylinositol 3,4,5-trisphosphate) and those regulating cGMP (Cyclic Guanosine 3,5-Monophosphate) and Myosin-II filament formation (Ref.3). Chemoattractants trigger a transient increase in cGMP. In most organisms, after its synthesis, cAMP remains inside the cells as cAMPi (Cyclic Adenosine 3,5-Monophosphate-Intracellular), where it binds and activates PKA (Protein Kinase-A). However, in D. discoideum, a significant fraction of cAMP is also secreted outside the cells as cAMPe (Cyclic Adenosine 3,5-Monophosphate-Extracellular), where it acts as a Chemoattractant by binding to Specific Surface Receptors or Chemoattractant Receptors called cARs (cAMP Receptors), that further enhances Chemotaxis along with G-Proteins (Guanine Nucleotide-Binding Proteins). Apart from cAMPe, Folic Acid as well as factors from Bacteria, serve as Chemoattractants. However cAMPe is the major effector (Ref.3 & 4).

GCs (Guanylyl Cyclases) are activated briefly by the G-Alpha, GBB (G-Beta) and G-Gamma subunits, the cGMP produced is rapidly degraded by a cGMP-induced, cGMP-specific PDE (Phosphodiesterase) called GBPA (cGMP-Stimulated cGMP-Specific Phosphodiesterase). Two GCs, GCA (Guanylyl Cyclase-A) and SGCA (Soluble Guanylate Cyclase) have been identified in D. discoideum. The intracellular cGMP that is produced on Chemotactic stimulation mediates the formation of Myosin-II filaments in D. discoideum (Ref.2). Downstream events include activation of two novel cGMP-binding proteins, GBPC (Cyclic GMP-Binding Protein-C) and GBPD (Cyclic GMP-Binding Protein-D) that mediate the cGMP effects. Activated GBPC and GBPD carry out two functions: First, the formation of Myosin-II filaments in the cortex at the rear of the cell inhibits pseudopod formation. Second, phosphorylation of RMLC (Myosin Regulatory Light Chain) through the activity of MLCK (Myosin Light Chain Kinase) enhances the traction force of Myosin-II filaments, which thereby causes the uropod to retract. MLCK phosphorylates Myosin-II. Filament formation is inhibited by several MHCKs (Myosin Heavy Chain Kinases). cGMP does not directly activate MHC (Myosin-II Heavy Chain), so MHCKs are proposed to be the first step in activation of this protein. cGMP is implicated in the transient phosphorylation of RMLC and MHC. In D. discoideum, cGMP is a main regulator of Myosin-II function, but PKA also controls it via cAMP mediated signaling (Ref.3 & 4).

During the cGMP peak induced by Chemotactic cAMP stimulation, the rate of Myosin-II dissociation is decreased. Following the peak of cGMP there is a transient increase in the rate of phosphorylation of Light and Heavy chains that had accumulated on the cytoskeleton, and the normal equilibrium is re-established. cGMP shifts in equilibrium in favour of association of Myosin-II on the cytoskeleton (Ref.3). Taken together, these studies suggest that cGMP is required to induce the Myosin-II filament formation at the rear of the cell, suppressing pseudopod formation at the lateral edges and back. The protrusion at the leading edge would not be very effective unless the back of the cell was retracted and pseudopodia at the sides of the cell were suppressed. This is mediated by Myosin-II filaments that are formed in these regions of the cell. In D. discoideum this occurs due to cGMP mediated Chemotaxis (Ref.4).

Knowledge from different systems such as mammalian Neutrophils and protozoan amoebae indicates that gradient sensing during Chemotaxis does not depend on a single molecular mechanism, but consists of several modules of inter-connected signalling networks. These networks achieve periodic pseudopod extension, directional sensing and polarization. However, there are still many unresolved issues regarding how and where pseudopodia are formed and how the spatially and temporally segregated molecular processes are integrated (Ref.3). Investigation of these issues requires methods to visualize the dynamics of activated components of larger complexes in moving cells. Ultimately the quantitative kinetic data with sufficient temporal and spatial resolution to develop models can integrate the various aspects of Chemotaxis (Ref.4).