The Phases of Signal Transduction
When an extra cellular molecule activates a cell surface receptor signal transduction is occurring. Due to this process the receptor alters intra-cellular molecules create a response.
There are 2 stages to this process:
Environmental Stimuli:
Because it is different depending on the complexity of the organism, sensing of the environment through the process of signal transduction is very important in the cells ability to react to the numerous environmental stimuli.
Receptors:
There is a rough division of receptors into 2 major classes, those being extra-cellular and intra-cellular.
Gene activations and metabolism alterations are examples of cellular responses to extra-cellular stimulation that require signal transduction. Gene activation leads to further cellular effects, since the products of responding genes include instigators of activation; transcription factors produced as a result of a signal transduction cascade can activate even more genes. Hence, an initial stimulus can trigger the expression of a large number of genes, leading to physiological events like the increased uptake of glucose from the blood stream and the migration of neutrophils to sites of infection. The set of genes and their activation order to certain stimuli is referred to as a genetic program.
Major Pathways
There are 2 stages to this process:
- 1) A specific receptor protein on the cell membrane is activated by a signaling molecule.
- 2) A second messenger transmits the signal into the cell, eliciting a physiological response.
Environmental Stimuli:
Because it is different depending on the complexity of the organism, sensing of the environment through the process of signal transduction is very important in the cells ability to react to the numerous environmental stimuli.
Receptors:
There is a rough division of receptors into 2 major classes, those being extra-cellular and intra-cellular.
- Extra-cellular: Extra-cellular receptors are integral trans-membrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside; the molecule does not pass through the membrane. This binding stimulates a series of events inside the cell; different types of receptor stimulate different responses and receptors typically respond to only the binding of a specific ligand. Upon binding, the ligand induces a change in the conformation of the inside part of the receptor. These result in either the activation of an enzyme in the receptor or the exposure of a binding site for other intra-cellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm.
- Intra-cellular receptors, such as nuclear receptors and cytoplasmic receptors, are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are lipophilic hormones like the steroid hormones testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the nuclear membrane into the nucleus, enabling gene transcription and protein production.
Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element (HRE) sequences, located in the promoter region of the genes activated by the hormone-receptor complex. Due to them enabling gene transcription, they are alternatively called inductors of gene expression. All hormones that act by regulation of gene expression have two consequences in their mechanism of action; their effects are produced after a characteristically long period of time and their effects persist for another long period of time, even after their concentration has been reduced to zero, due to a relatively slow turnover of most enzymes and proteins that would either deactivate or terminate ligand binding onto the receptor.
Signal transduction via these receptors involves little proteins, but the details of gene regulation by this method are not well understood. Nucleic receptors have DNA-binding domains containing zinc fingers and a ligand-binding domain; the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the receptor are usually hexameric repeats of any kind; the sequences are similar but their orientation and distance differentiate them. The ligand-binding domain is additionally responsible for dimerization of nucleic receptors prior to binding and providing structures for trans-activation used for communication with the translational apparatus.
Gene activations and metabolism alterations are examples of cellular responses to extra-cellular stimulation that require signal transduction. Gene activation leads to further cellular effects, since the products of responding genes include instigators of activation; transcription factors produced as a result of a signal transduction cascade can activate even more genes. Hence, an initial stimulus can trigger the expression of a large number of genes, leading to physiological events like the increased uptake of glucose from the blood stream and the migration of neutrophils to sites of infection. The set of genes and their activation order to certain stimuli is referred to as a genetic program.
Major Pathways
- These are some of the major signaling pathways, demonstrating how ligands binding to their receptors can affect second messengers and eventually result in altered cellular responses:
- MAPK/ERK pathway: A pathway that couples intra-cellular responses to the binding of growth factors growth factors to cell surface receptors. This pathway is very complex and includes many protein components. In many cell types, activation of this pathway promotes cell division, and many forms of cancer are associated with aberrations in it.
- cAMP dependent pathway: In humans, cAMP works by activating protein kinase A (PKA, cAMP-dependent protein kinase) and thus, further effects mainly depend on cAMP-dependent protein kinase, which vary based on the type of cell.
- IP3 DAG pathway: PLC cleaves the phospholipid phosphatidylinositol 4, 5-bisphosphate (PIP2) yielding diacyl glycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG remains bound to the membrane, and IP3 is released as a soluble structure into the cytosol. IP3 then diffuses through the cytosol to bind to IP3 receptors, particular calcium channels in the endoplasmic reticulum (ER). These channels are specific to calcium and only allow the passage of calcium to move through. This causes the cytosolic concentration of Calcium to increase, causing a cascade of intracellular changes and activity. In addition, calcium and DAG together works to activate PKC, which goes on to phosphorylate other molecules, leading to altered cellular activity. End effects include taste, manic depression, tumor promotion, etc.