Signal-transduction pathways initiated by binding of a signaling molecule to a cell surface receptor are often complex. In addition to the kinases and other enzymes mentioned above, the cascade of interacting molecules involved in communicating the signal within the cell can include various small, diffusible intracellular signaling molecules that act as intermediates in signal transduction. These are known as second messengers (the first messenger being the extracellular signaling molecule), see Table 1 for some examples.
Table1. EXAMPLES OF SECOND MESSENGERS IN CELL SIGNALING
Second messengers are a feature of pathways that use G-protein-coupled receptors (GPCRs). This large family of membrane-bound receptors (encoded by over 1000 genes in mammals) includes many receptors for prostaglandins and related lipids, various neurotransmitters, neuropeptides, and peptide hormones; other GPCRs are responsible for relaying the sensations of sight, smell, and taste.
GPCRs are distinguished by having a transmembrane domain that passes through the plasma membrane seven times and a cytoplasmic domain that can bind a G-protein. G-proteins are membrane-bound proteins with three subunits, α, β, and γ, extending into the cytoplasm, and are so called because the α subunit can bind GDP (keeping the G-protein inactive) or GTP. In the absence of ligand, a GPCR can bind an inactive G-protein (with GDP bound to its α subunit), but binding of ligand to the GPCR stimulates the G-protein by causing the α subunit to release GDP and bind GTP instead, causing the α subunit to dissociate from the βγ dimer and leading to activation of both (Figure 1A).
Fig1. Principles of G-protein signaling. (A) G-protein-coupled receptors (GPCRs) have seven transmembrane helices and a short cytoplasmic region bound by an associated G-protein with three subunits: α, β, and γ. Binding of ligand (L) to the extracellular domain of a GPCR activates its cytoplasmic domain and causes exchange of GTP for GDP on the G-protein. As a result, the Gα subunit is activated and dissociates from the Gβγ dimer, which in turn becomes activated. (B) The G-protein subunit Gαq uses various lipids and Ca2+ as second messengers. Activation of a type of G-protein α subunit known as Gαq causes it to bind and activate phospholipase C (PLC). Activated PLC then migrates along the plasma membrane to bind and cleave membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2 ). The reaction leaves a diacylglycerol (DAG) residue embedded in the membrane and liberates inositol 1,4,5-trisphosphate (IP3 ). The released IP3 diffuses to the endoplasmic reticulum, where it promotes the opening of an IP3-gated calcium ion channel, causing an efflux of Ca2+ from stores in the endoplasmic reticulum. With the help of Ca2+, the membrane-bound DAG activates protein kinase C (PKC), which is then recruited to the plasma membrane where it phosphorylates target proteins that differ according to cell type.
Each of the activated α and βγ units can then interact with proteins downstream in the signal-transduction pathway, and according to the type of G-protein, different second messengers can be involved in signal transduction. Some G-proteins stimulate or inhibit the membrane-bound enzyme adenylate cyclase, causing a change in intra cellular cyclic AMP (cAMP) levels. Other G-proteins stimulate the production of lipids (such as inositol 1,4,5-trisphosphate and diacylglycerol) and the release of calcium ions (Figure 1B). In turn, the second messengers activate downstream protein kinases such as cAMP-dependent protein kinase A and calcium-dependent protein kinase C, which go on to phosphorylate particular transcription factors, causing them to change their activity.
There is extensive crosstalk between different signaling pathways. At any moment, the response given by a particular cell depends on the sum of all signals that it receives and the nature of the receptors available to it.
