Heterologous Desensitization
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Heterologous desensitization (also known as cross-desensitization) is the term for the unresponsiveness of cells to one or more
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s to which they are normally responsive. Typically, desensitization is a
receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
-based phenomenon in which one receptor type, when bound to its ligand, becomes unable to further influence the signalling pathways by which it regulates cells and, in the case of cell surface membrane receptors, may thereafter be internalized. The desensitized receptor is degraded or freed of its activating ligand and re-cycled to a state where it is again able to respond to cognate ligands by activating its signalling pathways. This type of desensitization, termed homologous desensitization, leaves a cell transiently unresponsive to agents that activate the desensitized receptor but not to agents that activate other receptors. It commonly occurs with
G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
s where it is mediated by the G protein-coupled receptor kinases (GRK) and arestins that are mobilized during the receptor's activation. Homologous desensitization also occurs with cytokine and other types of receptors, such as those of the
epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor (biochemistry), receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligand (biochemistry ...
type, but in these cases desensitization is mediated by other types of receptor kinases. Homologous desensitization serves to limit or restrain a cell's responses to stimuli. However, some stimuli cause cells to activate
protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
that act to desensitize multiple types of receptors, thereby rendering a cell unresponsive to agonists of multiply receptor types. This commonly occurs with G protein coupled receptors (see
Protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
); cytokine and other non-G protein couple receptor types may also become heterologously desensitized by agents that activate protein kinase C but, perhaps more commonly, by agents that activate other protein kinases such as mitogen-activated protein kinase ( p38 MAP kinase). Heterologous desensitization may occur in cells that are grossly overstimulated for prolonged times by a certain agents. Receptor desensitization, whether heterologous or homologous, may contribute to human pathology. For example, excessive desensitization due to the overexpression of GRK2 leads to the loss of β-adrenergic receptor signaling in hearts (see Adrenergic receptor#β receptors]. β-Blockade and direct inhibition of GRK2 restores β-adrenergic receptor signaling and has been proven beneficial for the treatment of chronic heart failure in humans and animal models. On the other hand, inactivating mutations of GRK1 lead to faulty
rhodopsin Rhodopsin, also known as visual purple, is a protein encoded by the ''RHO'' gene and a G-protein-coupled receptor (GPCR). It is a light-sensitive receptor protein that triggers visual phototransduction in rod cells. Rhodopsin mediates dim ...
receptor desensitization and are linked to Oguchi disease, a non-progressive form of night blindness. Similarly,
single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
s in GRK4γ or that cause an increase in G protein-coupled receptor kinase (GRK) activity cause serine phosphorylation and uncoupling of the D1 receptor from its G protein effector GRK4. This impairs the kidney's renal sodium reabsorption,
diuresis Diuresis () is the excretion of urine, especially when excessive (polyuria). The term collectively denotes the physiologic processes underpinning increased urine production by the kidneys during maintenance of fluid balance. In healthy people, ...
, and excretion of sodium and water; it is associated with genetically based essential hypertension in humans and animal models.


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