5th February 2024

Cell Signal Proteins and Ion Channels

Cell signal receptors

Adhesion molecules

The interaction between a cell and its surroundings ( i.e. the extracellular matrix (ECM)) is heavily dependent on molecular interactions between the cell surface and extracellular molecules. This can be seen as either cell-cell interactions or cell-ECM component interactions.

These molecules are essential for basic physiological functions, including cell migration, cell growth, immunological processes, cell repair, embryogenesis and cell differentiation.

The important adhesion molecules covered in this topic include cadherins, immunoglobulin superfamily, selectins and integrins.

Cadherins

The cadherin superfamily consists of several molecules, including the desmogleins, desmocollins and cadherins. These molecules are dependent on calcium ions to enable their adhesive functions.

These molecules are essential in the embryological development of vertebrates by allowing accurate cell migration by differential expression of specific cadherin molecules. Cadherins are also crucial in maintaining normal cell structure and movement.

Immunoglobulin superfamily

This refers to a large family of cell surface proteins that contain an immunoglobulin domain. These molecules can mediate cell-cell adhesion without calcium ions.

These molecules are typically involved with cellular processes such as antigen presentation, white blood cell surface receptors and axonal development. Other Ig superfamily molecules act as integrin ligands ( e.g. ICAM).

Integrins

These are a group of transmembrane receptors that are heterodimers. These aid in the cell’s interaction with the ECM. These receptors typically bind to proteins in the ECM, including laminin, fibronectin and fibrinogen. However, some subsets will bind to immunoglobulins.

Some functions mediated by integrins include cell cycle regulation, apoptosis stimulation, cell cytoskeleton organisation, and cellular response to changes in the ECM. For example, the binding of WCC to antigens and platelet response to damaged blood vessels are mediated by integrins.

Certain genetic conditions like leukocyte adhesion deficiency are caused by deficiency of integrin subunits. In this condition, this prevents usual leukocyte expression of the β2 subunit, preventing extravasation of the leukocytes to sites of infection.

Selectin

Selectins are predominantly found on leukocytes, platelets and endothelial cells. These are expressed as part of the inflammatory response. This allows leukocytes to migrate to the site of inflammation and extravasate from blood vessels.

Reference

• Maitra, A., Kumar, V., Abbas, A. K., & Aster, J. C. (2013). Inflammation and Repair. In Robbin’s Basic Pathology (9th ed.): Elsevier.
• Norling, L., Leoni, G., Cooper, D., & Perretti, M. (2010). Cell Adhesion Molecules. In S. Ayoub (Author) & C. Serhan, P. Ward, & D. Gilroy (Eds.), Fundamentals of Inflammation (pp. 208-216). Cambridge: Cambridge University Press. doi:10.1017/CBO9781139195737.018
• Wong, E. V. (2021, Jan 3). 13: Extracellular matrix and cell adhesion. Biology LibreTexts. https://bio.libretexts.org/Bookshelves/Cell_and_Molecular_Biology/Book%3A_Cells_-_Molecules_and_Mechanisms_(Wong)/13%3A_Extracellular_Matrix_and_Cell_Adhesion
• Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Cell-Cell Adhesion. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26937/
• Mitchell, R. (2013). Blood Vessels. In Robbin’s Basic Pathology (9th ed.): Elsevier.

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/

Regulation of vascular tone

Vascular tone is controlled by several factors, including local and extrinsic factors (adrenaline, noradrenaline, acetylcholine, etc.). We will be focusing on the local factors. Agents in this group act as paracrine signalling agents to allow communication with adjacent cells. The vascular endothelium plays a vital role in controlling the vascular tone.

We will focus on the two most essential agents: nitric oxide and endothelin-1.

Nitric oxide

Nitric oxide is a potent vasodilator and is produced by nitric oxide synthase. This is produced from L-arginine and NADPH acting as electron donors. This eventually produces citrulline and nitric oxide. It has a relatively short half-life and acts locally to increase cellular concentrations of cGMP, activating other cellular processes.

Nitric oxide is also produced in other cells, including platelets, macrophages, neutrophils, hepatocytes and smooth muscle cells.

The function of nitric oxide includes:

• Microvascular tone control in organs
• Inhibition of platelet aggregation
• Vasodilation of the systemic circulation
• Neurotransmission
• Immune response is predominantly by phagocytes

Disorders resulting in imbalances in the production or generation of nitric oxide include hepatorenal syndrome, pulmonary hypertension, and CNS cell death.

Medication like nitro-glycerine is directly converted into nitric oxide by the body. Sildenafil acts to increase the levels of cGMP, which nitric oxide is responsible for producing through its action on guanylate cyclase.

Endothelin-1

Endothelin-1 is produced in response to vascular stresses, including shear forces, hypoxia and increased plasma volumes. Endothelin receptors induce vasoconstriction in most systemic circulation but result in vasodilation in the capillary beds.

Reference

• Maitra, A., Kumar, V., Abbas, A. K., & Aster, J. C. (2013). Inflammation and Repair. In Robbin’s Basic Pathology (9th ed.): Elsevier.
• Chapter 7. Vascular control. Mohrman D.E., & Heller L(Eds.), (2014). Cardiovascular Physiology, 8e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=843&sectionid=48779655