5th February 2024

Signal transduction

Cellular response to changes in their surrounding environment relies on communication of the external signal to the cell’s internal machinery. This often involves an external signal binding to one of these receptors. This forms an intermediate product that acts as a messenger. The intermediate product interacts with other proteins within the cell, leading to a final change in the state of the cell to respond to the external stimulus.

This system is required to allow cells to respond to change as the cell membrane prevents direct entry of the stimulus into the cell. Therefore, a secondary messenger is required to transmit this information to the internal cell mechanisms.

Types of receptors

Several receptors within the human body allow information transmission across the cell membrane:

• G-protein coupled receptor
• Voltage-gated/Ion-gated channel
• Protein kinase and phosphatase
• Nuclear hormones

G-protein coupled receptor

This is a ubiquitous cell surface receptor found across the body. These consist of a transmembrane protein that interacts with the G-protein intracellularly. In its inactive state, a GDP molecule is bound to the G-protein. A conformational change occurs when a suitable ligand binds to the transmembrane receptor, and the G-protein swaps its GDP for GTP. The α-subunit of the G protein dissociates from the remaining βγ-subunits. Both subunits can now interact with other intracellular proteins to allow the spread of signal transduction throughout the cell. The system is reset when GTP is hydrolysed into GDP, resulting in the α-subunit reuniting with the βγ-subunits.

G-proteins may exert an excitatory or inhibitory effect dependent on the target molecule that the G-protein subunit interacts with.

G-protein can interact with several secondary messenger molecules, including cAMP and phosphatidylinositol pathways.

G-protein coupled receptors are involved in various physiological functions, including visual and olfactory senses, homeostasis, autonomic nervous system transmission and effectors for several endocrine systems.

The G-protein coupled receptors’ dysfunction is linked with conditions like cholera, Albright’s hereditary osteodystrophy and retinitis pigmentosa.

Adapted from Original image from CNX OpenStax, CC BY 4.0 

Image Source: Open Oregon. Licensed under a creative commons license. Available for free at: https://openoregon.pressbooks.pub/mhccmajorsbio/chapter/types-of-receptors/ (Accessed: 21 December 2023).

Voltage-gated/Ion-gated ligand channels

Both channels are transmembrane proteins that allow ions to flow across a central pore through the cell membrane. The voltage-gated ion channels are governed by transmembrane voltage potential, while the ion-gated channels are controlled by specific ligands binding to the ion channel. When activated, the flow of ions across the channel results in excitation or inhibition of the cell.

Disorders of these ligand channels can result in several diseases, including hyperkalaemic and hypokalaemic periodic paralysis, hyperekplexia., long QT syndrome, myasthenia gravis, Lambert-Eaton myasthenic syndrome, Brugada syndrome and myotonia.

Protein kinase and phosphatase

These enzymes add a phosphate group to other proteins ( most commonly serine, threonine and tyrosine) to change the protein’s function. This leads to the eventual activation or deactivation of the protein.

Serine/threonine kinases regulate mitosis, cell differentiation and gene expression.

Tyrosine kinases make up many of the enzymes involved in the signalling for cell growth and differentiation, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), Epidermal growth factor (EGF) and insulin growth factor (IGF).

Nuclear hormones

Nuclear hormones rely on the ligand to pass directly into the cell and interact with intracellular receptors to exert change. This typically binds to an intracellular protein before migrating into the cell nucleus. The complex binds to specific regions of the DNA to alter DNA expression.

Examples of such hormones include steroid hormones, vitamin D and retinoic acids.

Reference

• Maitra, A., Kumar, V., Abbas, A. K., & Aster, J. C. (2013). Inflammation and Repair. In Robbin’s Basic Pathology (9th ed.): Elsevier.
• Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. Pathways of Intracellular Signal Transduction. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9870/
• Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. General Principles of Cell Communication. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26813/