G protein-coupled receptors and the modification of FcepsilonRI-mediated mast cell activation

Abstract

By releasing multiple pro-inflammatory mediators upon activation, mast cells are critical effector cells in the pathogenesis of allergic inflammation. The traditional viewpoint of antigen-dependent mast cell activation is that of a Th(2)-driven process whereby antigen-specific IgE molecules are produced by B cells followed by binding of the IgE to high affinity IgE receptors (FcepsilonRI) expressed on mast cells. Subsequent antigen-dependent aggregation of the FcepsilonRI initiates an intracellular signalling cascade that culminates in mediator release. Mast cell responses, including cell growth, survival, chemotaxis, and cell adhesion, however, can also be regulated by other receptors expressed on mast cells. Furthermore, FcepsilonRI-mediated mast cell mediator release can be significantly modified by ligation of specific classes of these receptors. One such class of receptors is the G protein-coupled receptors (GPCR). In this review, we describe how sub-populations of GPCRs can either enhance or inhibit FcepsilonRI-mediated mast cell activation depending on the particular G protein utilized for relaying signalling. Furthermore, we discuss the potential mechanisms whereby the signalling responses utilized by the FcepsilonRI for mast cell activation are influenced by those initiated by GPCRs to produce these diverse responses.

Fig 1

Major classes of GPCRs and the signals relayed by the respective Gα subunits.

Fig 2

The respective balance between G_i- and G_s-dependent signalling pathways and their roles in the modification of FcαRI-mediated mast cell degranulation. For clarity, many of the intermediary steps in the FcαRI-dependent signalling pathway have been omitted. For further details concerning this pathway and the pathways regulating cytokine production and eicosanoid release, the readers are referred to the text and references [6, 101]. FcαRI aggregation leads to the phospholipase Cγ (PLCγ)-mediated production of diaclglycerol (DAG) and inositol trisphosphate (IP₃) which respectively activate protein kinase C (PKC) and mobilize calcium from intracellular stores, essential signals for degranulation. Phosphoinositide 3-kinase (PI3K), primarily the p110δ subunit, contributes to a maintained calcium signal partly through the Bruton’s tyrosine kinase (Btk)-dependent enhancement of PLCγ activation. G_i-coupled receptors impact these events positively by downregulating the production of cyclic adenosine monophosphate (cAMP) which is a negative signal for mast cell activation and by promoting the activation of PI3Kγ and PLCβ. In contrast G_s-coupled receptors impact FcεRI-mediated mast cell activation by enhancing the production of cAMP which, via activation of protein kinase A (PKA), inhibits mast cell activation by an, as yet, unknown mechanism. S1P₂ and P2Y which are coupled to G_q-to induce calcium flux and result in degranulation (not shown in this figure). The green lines and positive symbols designate activating signalling pathways and the red lines and -symbols represent inhibiting signalling pathways.