Remix education

Regulation of Receptors :- Up Regulation and Down Regulation

Regulation of Receptors

         Cells can increase (up regulate) or decrease (down regulate) the number of receptors to a given hormone or neurotransmitter to alter their sensitivity to different molecules. This is a locally acting feedback mechanism.
         All living cells have the ability to receive the process signals which originate outside their membranes, which they do by means of receptors, usually found on a cell’s surface embedded in the cell membrane. When such signals bind to a receptor, they effectively direct the cell to do an activity, such as dividing, dying or allowing substances to be created, or to enter or exit the cell. A cell’s ability to respond to a chemical message depends on the presence of receptors tuned to that message. The more receptors a cell has that are tuned to the message, the more the cell will respond to it. Receptors are created, or expressed by the DNA of the cell, and they can be increased or up regulated when the signal is weak, or decreased/down regulated, when it is strong.
(i) Up Regulation
         Up regulation involves increase in the number of receptors due to external stimulation. An example of up regulation is the response of liver cells exposed to molecules like dioxin. In this situation, the cells increase their production of cytochrome P 450 enzyme, which in turn increases their degradation of these molecules. Up regulation results in super-sensitized cells especially after repeated exposure to an antagonist drug or prolonged absence of the agonist.
(ii) Down Regulation
         Down regulation involves decrease in the quantity of cellular component, such as RNA or protein, in response to an external stimulus. It happens when receptors have been chronically exposed to an excessive amount of neurotransmitters, whether endogenous or in the form of drugs. This results in ligand-induced desensitization or internalisation of that receptor. It is usually exhibited by various hormonal receptors. An example of insulin receptor down regulation can be cited here.

         Elevated levels of insulin in the blood, trigger down regulation of the associated receptors. When insulin binds to its receptors on the surface of the cell, the hormonereceptor complex undergoes endocytosis and is subsequently attacked by intracellular lysosomal enzymes. Internalisation of the insulin molecule provides a pathway for the degradation of the hormone as well as for regulation of the number of sites which 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 internalisation 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 the period of time, this self-induced loss of target cell receptors for insulin reduces the target cell’s sensitivity to the elevated hormone concentration.
          Due to elevated levels of blood glucose in an overweight individual, the β-cells in the pancreas must release more insulin 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 the hormone. There is also a hepatic decrease in sensitivity to insulin. This can be seen in continuing gluconeogenesis in the liver even when blood glucose levels are elevated. This is responsible for insulin resistance. Thus, insulin receptor down regulation helps in explaining Pathophysiology of diabetes.
          Some receptor agonists may cause down regulation of their respective receptors, while most receptor antagonists temporarily up regulate their respective receptors. The disequilibrium caused by these changes often causes withdrawal when the long-term use of a drug is discontinued. However, use of certain receptor antagonists may damage receptors faster than they up regulate. Down regulation of receptors happens when receptors have been chronically exposed to an excessive amount of neurotransmitters. This results in ligand-induced desensitization. It is usually exhibited by various hormone receptors. Up regulation of receptors results in super-sensitized cells especially after repeated exposure to an antagonist or prolonged absence of agonist. Receptors are created, or expressed, by the DNA of the cell and they can be increased or up regulated, when the signal is weak or decreased or down regulated when the signal is strong.