Downregulation and upregulation
Encyclopedia
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) or the increased numbers of NMDA glutamate receptors found in people who have consumed excessive quantities of alcohol
(thereby inhibiting those same receptors).
Upregulation and downregulation can also happen as a response to toxins or hormones, for example in pregnancy hormones cause cells in the uterus become more sensitive to oxytocin
.
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.
s in a person with type 2 diabetes. 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. 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 down regulate 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.
In general, receptor up/down-regulation at brain level (humans) can vary from few days to weeks, growing new axons between neurons more than 4 weeks and reaching the final balance can sometimes take as long as 6 months.
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
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
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
to a molecule, such as a hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
or neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
, which reduces the cell's sensitivity to the molecule. This phenomenon is an example of a locally acting negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
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) or the increased numbers of NMDA glutamate receptors found in people who have consumed excessive quantities of alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
(thereby inhibiting those same receptors).
Upregulation and downregulation can also happen as a response to toxins or hormones, for example in pregnancy hormones cause cells in the uterus become more sensitive to oxytocin
Oxytocin
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
.
Mechanism: The Insulin Receptor
The process of downregulation occurs when there are elevated levels of the hormone insulinInsulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
in the blood. When insulin binds to its receptors on the surface of a cell, the hormone receptor complex undergoes endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
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
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of new receptors within the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
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 cellTarget cell
-Hematology:In hematology, target cells are very abnormal red blood cells, that have a bullseye appearance . These target cells are associated with Hemoglobin C disease, Asplenia, Liver Disease, Thalassemia and severe Iron deficiency anemia...
s in a person with type 2 diabetes. Due to the elevated levels of blood glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
in an overweight individual, the β-cells
Beta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...
(islets of Langerhans
Islets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
) in the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
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 down regulate 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
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
. This can be seen in the continuing gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
in the liver even when blood glucose levels are elevated. This is the more common process of insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
, which leads to adult-onset diabetes.
Another example can be seen in diabetes insipidus
Diabetes insipidus
Diabetes insipidus is a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine. There are several different types of DI, each with a different cause...
, 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.In general, receptor up/down-regulation at brain level (humans) can vary from few days to weeks, growing new axons between neurons more than 4 weeks and reaching the final balance can sometimes take as long as 6 months.