The mechanism of hormone action

For any hormone to exert its biological effect it must interact with its own specific receptor. The receptor, usually a large protein molecule, has a unique three-dimensional shape that will only bind a particular hormone or analogs of that hormone {compounds which possess a chemical structure which is very similar to the hormone concerned). As will be seen later, the receptor sites for hormones are located in either the cell membranes or the cytoplasm of cells. The specificity of hormone action, that is, the fact that only particular cells will be affected by a particular hormone, is determined by the presence or absence of receptors for that hormone in a given cell. If the receptor is absent from a cell then that cell is unresponsive to the hormone. This explains why hormones released into the general circulation have effects on specific cells, rather than more general effects on all cells as may be expected by their presence in the body fluids as a whole.

Membrane bound receptors

Hormones which have a peptide or protein structure and most of the amino acid derivatives combine with receptors that are located in the plasma membrane of the target cells. As will be seen later, the hormone ― receptor interaction results in some change in cellular function. Such molecules ― peptides, proteins and amino acid derivatives ― are hydrophilic in nature, easily dissolving in aqueous solvents such as body fluids. This implies that their solubility in organic solvents is low. In order to exert their effect and produce a biological response, the hormone somehow has to influence the functioning of the target cell. Given the chemical nature of these hormones, they would be unable to cross the plasma membrane to influence cellular processes and therefore require a receptor located in the cell membrane.

The hormone binds to its membrane receptor, rather like a key fits into a lock. In doing so, it is said to produce an activated receptor which triggers a series of biochemical reactions that leads to the production of a biological response (), The initial step in this series of reactions is the activation of another membrane bound protein called a G protein. (In actual fact there are many different types of G protein, but that need not be of any concern at the moment.) G proteins are actually trimers, i.e. they consist of three subunits. One of these subunits binds the substance guanosine diphosphate (GDP) at rest, hence the name G protein. However, activation of the G protein by a hormone-receptor complex causes the phosphorylation of guanosine diphosphate to produce gaunosine triphosphate (GTP). This produces a conformational change in the G protein and, as consequence, the G protein dissociates, splitting into its constituent subunits. The subunit which has the gaunosine triphosphate bound to it activates another membrane bound enzyme called adenylate cyclase. GTP is eventually converted back to GDP by the GTPase activity of the G protein, and as a consequence the G protein returns to its original conformation. This process takes several seconds and allows the activation of many molecules of adenylate cyclase. Adenylate cyclase removes phosphate groups from ATP to form cAMP (cyclic adenosine monophosphate) (). The function of cyclic adenosine monophosphate is to activate another enzyme called a protein kinase. Having done this, the cyclic adenosine monophosphate is broken down to AMP by the enzyme phosphodiesterase. Kinases are enzymes which phosphorylate other molecules, and the activated protein kinase ‘looks’ for a substance to phosphorylate. It is this final phosphorylation which produces the biological response to the initial hormone binding to the cell. The substances phosphorylated are proteins, and the effect of phosphorylation is to alter their conformation. If the protein is, say, an ion channel, then phosphorylation may well cause it to alter from its closed state to its open state. This will result in the movement of ions across the membrane which gives the desired response. For example, Ca2+ ions may enter the cell via Ca2+ channels and the resultant increase in intracellular calcium concentration may, for example, cause the cell to secrete some substance, or to contract ― whatever response is appropriate for that cell. Listed below are other processes which may be altered by hormones in this way.

  • • Activation of enzymes, e.g. certain metabolic pathways may be switched on.
  • • Activation of active transport mechanisms, e.g. substances may be taken up into the cell.
  • • Activation of microtubule formation. This may be the initial step in the secretion of substances.
  • • DNA metabolism may be altered. This may be important in the growth or division of cells.

In the process described above, cyclic adenosine monophosphate is termed a second messenger molecule, the hormone being the first messenger. It is now known that many other substances are able to function as second messenger molecules within cells. For example, hormone-receptor interaction may result in the activation of the membrane-bound enzyme phospholipase C. This enzyme in turn promotes the breakdown of the membrane lipid phosphatidyl inositol bisphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate (IP3), both of which function as second messenger molecules. IP3 diffuses into the interior of the cell where it promotes the release of Ca2+ from intracellular stores, e.g. the endoplasmic reticulum, or the sarcoplasmic reticulum in muscle cells. DAG remains in the membrane and in turn activates another enzyme called protein kinase C. Protein kinase C functions in the same way as the kinases described previously ― once activated it will phosphorylate a substrate molecule. In this process, it is possible to consider the released Ca2+ as a third messenger molecule because it goes on to mediate several biological effects.

Hormones using cytosolic receptors

The steroid hormones and some amino acid-derived hormones (e.g. thyroxine released from the thyroid gland in mammals), utilize cytosolic receptors as opposed to membrane-bound receptors. These hormones are highly lipid soluble and pass very easily across the plasma membrane of target cells. There is some debate as to how these hormones produce a biological response, but it is thought that the hormone arrives at the target cell in conjunction with some sort of carrier molecule. Since the molecule is lipid soluble, it is unable to dissolve in the aqueous body fluids of animals. Thus, it combines with a carrier molecule, and it is this hormone carrier complex which is transported around in the body fluids of the animal. The hormone dissociates from the carrier molecule and freely enters the target cell. In the cytoplasm of the target cell the hormone combines with its specific receptor. Interaction between the hormone and its receptor results in an activated hormone-receptor complex. The activated receptor-hormone complex has a high affinity for DNA. This complex enters the nucleus where it combines with receptors associated with the DNA and it initiates changes in DNA transcription. The nature of the receptor site on the DNA molecule is not fully established, but it is thought that binding takes place in a region of the DNA known as the promoter region. By binding to this region of the DNA, it is possible to switch a particular gene on or off.

Overall, the function of steroid hormones is to stimulate or repress the production of proteins ― they are capable of turning genes on and off. The proteins that are then produced modify biochemical processes in the cell, thus producing the biological effect of the hormone. For example, the protein produced may be an enzyme that influences the metabolism of the cell. This may mean that a particular metabolic pathway within the cell can be switched on or off. Although, in some senses, it is a simpler way of producing the biological effect of the hormone, the action of steroid hormones tends to be slower than that of hormones which have a membrane-bound receptor.