14.12: Intracellular Signaling Cascades

Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. The continuation of a signal in this manner is called signal transduction. Signal transduction only occurs with cell-surface receptors, which cannot interact with most components of the cell, such as DNA. Only internal receptors can interact directly with DNA in the nucleus to initiate protein synthesis. When a ligand binds to its receptor, conformational changes occur that affect the receptor's intracellular domain. Conformational changes of the extracellular domain upon ligand binding can propagate through the membrane region of the receptor and lead to activation of the intracellular domain or its associated proteins.

After the ligand binds to the cell-surface receptor, the activation of the receptor's intracellular components sets off a chain of events that is called a signaling pathway or a signaling cascade. In a signaling pathway, second messengers–enzymes–and activated proteins interact with specific proteins, which are then activated in a chain reaction that eventually leads to a change in the cell's environment, such as an increase in metabolism or specific gene expression. The events in the cascade occur in a series like how a current flows in a river. Interactions that occur before a certain point are defined as upstream events, and events after that point are called downstream events.

Signaling pathways can get very complicated very quickly because most cellular proteins can affect different downstream events, depending on the conditions within the cell. A single pathway can branch off toward different endpoints based on the interplay between two or more signaling pathways, and the same ligands are often used to initiate different signals in different cell types. This variation in response is due to differences in protein expression in different cell types. Another complicating element is signal integration of the pathways, in which signals from two or more different cell-surface receptors merge to activate the same response in the cell. This process can ensure that multiple external requirements are met before a cell commits to a specific response.

The effects of extracellular signals can also be amplified by enzymatic cascades. At the initiation of the signal, a single ligand binds to a single receptor. However, activation of a receptor-linked enzyme can activate many copies of a component of the signaling cascade, which amplifies the signal.

This text is adapted from Openstax, Biology 2e, Section 9.2: Propagation of the Signal.

Intracellular signaling cascades or pathways relay extracellular signals to the cell interior.

Multiple intracellular signaling cascades, such as the cyclic AMP, MAPK/ERK, and IP3/DAG pathways, transmit and amplify the signals, leading to cellular responses including changes in gene expression or cell metabolism. 

For example, the cyclic AMP signaling cascade can be triggered by various external ligands, such as adrenaline, that bind to transmembrane G protein-coupled receptors.

The binding creates a conformational change in the receptor that enables GDP/ GTP exchange and dissociation of the G protein subunits.

This stimulates the enzyme adenylyl cyclase to convert ATP  into cyclic AMP. Once stimulated, adenylyl cyclase can generate multiple cyclic AMP molecules, resulting in the amplification of the signal.

Cyclic AMP molecules can activate protein kinase A or PKA molecules. This enzyme phosphorylates many other proteins,  including transcription factors that regulate gene expression.