Downregulation and upregulation

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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 (resulting in greater
degradation of these molecules).
Most receptor agonists downregulate their respective receptor(s), while most receptor
antagonists 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.
Upregulation and downregulation can also happen as a response to toxins or hormones. An
example of upregulation in pregnancy, is hormones cause cells in the uterus to become more
sensitive to oxytocin.

Contents

1 Receptor downregulation
o 1.1 Mechanism: The Insulin Receptor
o 1.2 Cases
o 1.3 Reversal

2 See also

3 References

4 External links

Receptor downregulation

Mechanism: The Insulin Receptor

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 cells 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 -cells
(islets of Langerhans) 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 subjects resistance by decreasing sensitivity to this hormone. There is
also a hepatic decrease in sensitivity to insulin. This can be seen in