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 phenomenon 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.
Some receptor agonists may cause downregulation of their respective receptor(s), while most
receptor antagonists may temporally upregulate their respective receptor(s).
The disequilibrium caused by these changes often causes withdrawal when the long-term
use of a medication or drug is discontinued.
However, the use of certain receptor antagonists may also damage receptors faster than they
upregulate.
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.
Receptor downregulation Insulin receptor mechanism
The process of downregulation occurs when there are elevated levels of the hormone insulin
in the blood.
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.
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.
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.
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.
The process of decreasing the number of receptor sites is virtually the same for all hormones;
it varies only in the receptor hormone complex.
Cases This process is illustrated by the insulin
receptor sites on target cells in a person with type 2 diabetes.
Due to the elevated levels of blood glucose in an overweight individual, the β-cells
in the pancreas must release more insulin than normal to meet the demand and return
the blood to homeostatic levels.
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.
Another example can be seen in diabetes insipidus, in which the kidneys become insensitive to
arginine vasopressin.
Reversal The process of downregulation can be counteracted
in the above example.
A person with type 2 diabetes can increase their sensitivity to insulin through proper
diet and regular exercise, resulting in weight loss; some individuals may even return to
their pre-diabetic state by following such a regimen.
See also Regulation of gene expression
Desensitization References
Sherwood, L..
“Human Physiology From Cells to Systems, 5th Ed”.
Belmont, CA: Brooks/Cole-Thomson Learning Wilmore, J., Costill, D..
Physiology of Sport and Exercise, 3rd Ed.
Champaign, IL: Human Kinetics External links
Down-Regulation at the US National Library of Medicine Medical Subject Headings