3-2 G-protein-coupled receptors on phagocytes link microbe recognition with increased efficiency of intracellular killing.
Phagocytosis of microbes by macrophages and neutrophils is generally followed by the death of the microbe inside the phagocyte. As well as the phagocytic receptors, macrophages and neutrophils have other receptors that signal to stimulate antimicrobial killing. These receptors belong to the evolutionarily ancient family of G-protein-coupled receptors (GPCRs), which are characterized by seven membrane-spanning segments. Members of this family are crucial to immune system function because they also direct responses to anaphylatoxins such as the complement fragment C5a (see Section 2-14) and to many chemokines, recruiting phagocytes to sites of infection and promoting inflammation.
The fMet-Leu-Phe (fMLF) receptor is a G-protein-coupled receptor that senses the presence of bacteria by recognizing a unique feature of bacterial polypeptides. Protein synthesis in bacteria is typically initiated with an N-formylmethionine (fMet) residue, an amino acid present in prokaryotes but not in eukaryotes. The fMLF receptor is named after a tripeptide, formylmethionyl-leucyl phenylalanine, for which it has a high affinity, although it also binds other peptide motifs. Bacterial polypeptides binding to this receptor activate intracellular signaling pathways that direct the cell to move toward the most concentrated source of the ligand. Signaling through the fMLF receptor also induces the production of microbicidal reactive oxygen species (ROS) in the phagolysosome. The C5a receptor recognizes the small fragment of C5 generated when the classical or lectin pathways of complement are activated, usually by the presence of microbes (see Section 2-14), and signals by a similar pathway as the fMLF receptor. Thus, stimulation of these receptors both guides monocytes and neutrophils toward a site of infection and leads to increased antimicrobial activity; these cell responses can be activated by directly sensing unique bacterial products or by messengers such as C5a that indicate previous recognition of a microbe.
The G-protein-coupled receptors are so named because ligand binding activates a member of a class of intracellular GTP-binding proteins called G proteins, sometimes referred to as heterotrimeric G proteins to distinguish them from the family of ‘small’ GTPases typified by Ras. Heterotrimeric G proteins are composed of three subunits: Gα, Gβ, and Gγ, of which the α subunit is similar to the small GTPases (Fig. 3.3). In the resting state, the G protein is inactive, not associated with the receptor, and a molecule of GDP is bound to the α subunit. Ligand binding induces conformational changes in the receptor that allow it to bind the G protein, which results in the displacement of the GDP from the G protein and its replacement with GTP. The active G protein dissociates into two components, the Gα subunit and a complex consisting of a Gβ and a Gγ subunit. Each of these components can interact with other intracellular signaling molecules to transmit and amplify the signal. G proteins can activate a wide variety of downstream enzymatic
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