Downregulation and upregulation

Downregulation and Upregulation of Receptors - Overview

Downregulation of receptors happens when receptors have been chronically exposed to an excessive amount of neurotransmitters, whether endogenous or drugs. This results in ligand-induced desensitization or internalization of that receptor. It is usually exhibited by various hormone receptors. Upregulation of receptors, on the other hand, results in super-sensitized receptors especially after repeated exposure to the drug.

Within the regulation of gene expression, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable. An increase of a cellular component is called upregulation.

An example of downregulation is the cellular decrease in the number of receptors to a molecule, such as a hormone or neurotransmitter, which reduces the cell's sensitivity to the molecule. This is an example of a locally acting negative feedback mechanism.

An example of upregulation is the increased number of cytochrome P450 enzymes in liver cells when xenobiotic molecules such as dioxin are administered, resulting in greater degradation of these molecules.

Some receptor agonists may cause downregulation of their respective receptors, while most receptor antagonists temporarily upregulate their respective receptors. The disequilibrium caused by these changes often causes withdrawal when the long-term use of a drug is discontinued. However, the use of certain receptor antagonists may also damage receptors faster than they upregulate (internalization of receptors due to antagonism).

Upregulation and downregulation can also happen as a response to toxins or hormones. An example of upregulation in pregnancy is hormones that cause cells in the uterus to become more sensitive to oxytocin.

Example : Insulin receptor downregulation

The process of downregulation occurs when there are elevated levels of the hormone insulin in the blood.[1] When insulin binds to its receptors on the surface of a cell, the hormone receptor complex undergoes endocytosis and is subsequently attacked by intracellular lysosomal enzymes.[2] The internalization of the insulin molecules provides a pathway for degradation of the hormone as well as for regulation of the number of sites that are available for binding on the cell surface.[3] At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding.[4] The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cell's sensitivity to the elevated hormone concentration.[4]

This process is illustrated by the insulin receptor sites on target cells in a person with type 2 diabetes.[5] Due to the elevated levels of blood glucose in an overweight individual, the β-cells (islets of Langerhans) in the pancreas must release more insulin than normal to meet the demand and return the blood to homeostatic levels.[6] The near-constant increase in blood insulin levels results from an effort to match the increase in blood glucose, which will cause receptor sites on the liver cells to downregulate and decrease the number of receptors for insulin, increasing the subject’s resistance by decreasing sensitivity to this hormone. There is also a hepatic decrease in sensitivity to insulin. This can be seen in the continuing gluconeogenesis in the liver even when blood glucose levels are elevated. This is the more common process of insulin resistance, which leads to adult-onset diabetes.[7]

Another example can be seen in diabetes insipidus, in which the kidneys become insensitive to arginine vasopressin.

See also

References

  1. ↑ "On the Mechanism of Ligand-induced Down-Regulation of Insulin Receptor Level in the Liver Cel". The Journal of Biological Chemistry. 256.
  2. ↑ Zaliauskiene, Lolita; Kang, Sunghyun; Brouillette, Christie G.; Lebowitz, Jacob; Arani, Ramin B.; Collawn, James F. (2016). "Down-Regulation of Cell Surface Receptors Is Modulated by Polar Residues within the Transmembrane Domain". Molecular Biology of the Cell. 11 (8): 2643–2655. ISSN 1059-1524. PMC 14946Freely accessible. PMID 10930460.
  3. ↑ Carpentier, J.-L. "Insulin receptor internalization: molecular mechanisms and physiopathological implications". Diabetologia. 37 (2): S117–S124. doi:10.1007/BF00400835. ISSN 0012-186X.
  4. 1 2 Sherwood, Lauralee; Klandorf, Hillar; Yancey, Paul (2012-01-01). Animal Physiology: From Genes to Organisms. Cengage Learning. ISBN 1133709516.
  5. ↑ Fröjdö, Sara; Vidal, Hubert; Pirola, Luciano (2009-02-01). "Alterations of insulin signaling in type 2 diabetes: A review of the current evidence from humans". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1792 (2): 83–92. doi:10.1016/j.bbadis.2008.10.019.
  6. ↑ Wilcox, Gisela (2016-11-20). "Insulin and Insulin Resistance". Clinical Biochemist Reviews. 26 (2): 19–39. ISSN 0159-8090. PMC 1204764Freely accessible. PMID 16278749.
  7. ↑ "Protein Controversies in Diabetes". journal.diabetes.org. Retrieved 2016-11-20.

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External links

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