Although hormones can exert coordinated, pleiotropic control on multiple aspects of cell function, any given hormone does not regulate every function in every cell type. Rather, a single hormone controls a subset of cellular functions in only the cell types that express receptors for that hormone. Thus selective receptor expression determines which cells respond to a given hormone. Moreover, the differentiated state of a cell determines how it responds to a hormone. Thus the specificity of hormonal responses resides in the structure of the hormone itself, the receptor for the hormone, and the cell type in which the receptor is expressed. Serum hormone concentrations are typically extremely low (10−11 to 10−9 mol/L). Therefore, a receptor must have high affinity, as well as specificity, for its cognate hormone.
How does hormone-receptor binding get transduced into a cellular response? Hormone binding to a receptor induces conformational changes in the receptor. These changes are collectively referred to as a signal. The signal is transduced into the activation of one or more intracellular messengers. Messenger molecules then bind to effector proteins, which in turn modify specific cellular functions. The combination of hormone-receptor binding (signal), activation of messengers (transduction), and regulation of one or more effector proteins is referred to as a signal transduction pathway (also called simply a signaling pathway), and the final outcome is referred to as the cellular response.
Signaling pathways are usually characterized by the following properties: 1.
Multiple, hierarchical steps in which “downstream” effector proteins are dependent on and driven by “upstream” receptors, transducers, and effector proteins. This means that loss or inactivation of one or more components within the pathway leads to general resistance to the hormone, whereas constitutive activation or overexpression of components can drive a pathway in an unregulated manner.
2.
Amplification of the initial hormone-receptor binding. Amplification can be so great that maximal response to a hormone is achieved when the hormone binds to a small percentage of receptors.
3.
Activation of multiple pathways, or at least regulation of multiple cell functions, from one hormone-receptor binding event. For example, binding of insulin to its receptor activates three separate signaling pathways. Even in fairly simple pathways (e.g., glucagon activation of adenylate cyclase), divergent downstream events allow the regulation of multiple functions (e.g., post-translational activation of glycogen phosphorylase and increased phosphoenolpyruvate carboxykinase gene transcription).
4.
Antagonism by constitutive and regulated negative feedback reactions. This means that a signal is dampened or terminated (or both) by opposing reactions and that loss or gain of function of opposing components can cause hormone-independent activation of a specific pathway or hormone resistance. As discussed in , hormones signal to cells through membrane or intracellular receptors. Membrane receptors have rapid effects on cellular processes (e.g., enzyme activity, cytoskeletal arrangement) that are independent of the synthesis of new protein. Membrane receptors can also rapidly regulate gene expression through either mobile kinases (e.g., cyclic adenosine monophosphate–dependent protein kinase [PKA], mitogen-activated protein kinases [MAPKs]) or mobile transcription factors (e.g., signal transducer and activator of transcription proteins [STATs], Mothers against decapentaplegic homologs [Smads]). Steroid hormones have slower, longer term effects that involve chromatin remodeling and changes in gene expression. Increasing evidence indicates that steroid hormones have rapid, nongenomic effects as well, but these pathways are still being elucidated.