Receptor–ligand interaction is usually just the beginning of the cell response. This event is transduced into secondary responses within the cell that can be divided into four broad categories: (1) ion channel activation, (2) G-protein activation, (3) activation of enzyme activity within the cell, or (4) direct activation of transcription. Within each of these groups, responses can be quite varied. Some of the common mechanisms by which chemical messengers exert their intracellular effects are summarized in Table 1. Ligands such as acetylcholine bind directly to ion channels in the cell membrane, changing their conductance. Thyroid and steroid hormones, 1,25-dihy droxycholecalciferol, and retinoids enter cells and act on one or another member of a family of structurally related cytoplasmic or nuclear receptors. The activated receptor binds to DNA and increases transcription of selected mRNAs. Many other ligands in the ECF bind to receptors on the surface of cells and trigger the release of intracellular mediators such as cAMP, inositol trisphosphate (IP3 ), and DAG that initiate changes in cell function. Consequently, the extracellular ligands are called “first messengers” and the intracellular mediators are called “second messengers.” Second messengers bring about many short-term changes in cell function by altering enzyme function, triggering exocytosis, and so on, but they also can lead to the alteration of transcription of various genes. A variety of enzymatic changes, protein–protein interactions, or second messenger changes can be activated within a cell in an orderly fashion following receptor recognition of the primary messenger. The resulting cell signaling pathway provides amplification of the primary signal and distribution of the signal to appropriate targets within the cell. Extensive cell signaling pathways also provide opportunities for feedback and regulation that can fine-tune the signal for the correct physiologic response by the cell.
Table1. Common mechanisms by which chemical messengers in the ECF bring about changes in cell function.
The most predominant posttranslation modification of proteins, phosphorylation, is a common theme in cell signaling pathways. Cellular phosphorylation is under the control of two groups of proteins: kinases, enzymes that catalyze the phosphorylation of tyrosine or serine and threonine residues in proteins (or in some cases, in lipids); and phosphatases, proteins that remove phosphates from proteins (or lipids). Some of the larger receptor families are themselves kinases. Tyrosine kinase receptors initiate phosphorylation on tyro sine residues on complementary receptors following ligand binding. Serine/threonine kinase receptors initiate phosphorylation on serines or threonines in complementary receptors following ligand binding. Cytokine receptors are directly associated with a group of protein kinases that are activated following cytokine binding. Alternatively, second messenger changes can lead to phosphorylation further downstream in the signaling pathway. More than 500 protein kinases have been described. Some of the principal ones that are important in mammalian cell signaling are summarized in Table 2. In general, addition of phosphate groups changes the conformation of the proteins, altering their functions and consequently the functions of the cell. The close relationship between phosphorylation and dephosphorylation of cellular proteins allows for a temporal control of activation of cell signaling pathways. This is sometimes referred to as a “phosphate timer.” The dysregulation of the phosphate timer and subsequent cellular signaling in a cell can lead to disease (Clinical Box 2–7).
Table2. Sample protein kinases.
