Heterologous desensitisation

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Heterologous desensitization (also known as cross-desensitization) is the term for the unresponsiveness of cells to one or more agonists to which they are normally responsive. Typically, desensitization is a Receptor (biochemistry)-based phenomenon in which one receptor type, when bound to its ligand, becomes unable to further influence the signaling 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 signaling 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 receptors where it is mediated by the G protein-coupled receptor kinases (GRK) and arestins that are mobilized during the receptor's activation.[1] Homologous desensitization also occurs with cytokine and other types of receptors such as those of the epidermal growth factor receptor type but in these cases desensitization is mediated by other types of receptor kinases.[2] Homologous desensitization serves to limit or restrain a cells responses to stimuli. However, some stimuli cause cells to active protein kinase Cs which 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#Function);[3] cytokine and other non-G protein couple receptor types may also become heterologously desensitized by agents which activate protein kinase C but, perhaps more commonly, by agents that activate other protein kinases such as mitogen-activated protein kinase (p38 MAP kinase).[2] Heterologous desensitization may also occur in cells that are grossly over-stimulated for prolonged times by a certain agents.[4]

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 as well as animal models. On the other hand, inactivating mutations of GRK1 lead to faulty rhodopsin receptor desensitization and are linked to Oguchi disease, a non-progressive form of night blindness. Similarly, single nucleotide polymorphisms 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, and excretion of sodium and water and is associated with genetically based essential hypertension in humans as well as animal models.[5][6]


  1. ^ Han CC, Ma Y, Li Y, Wang Y, Wei W (2016). "Regulatory effects of GRK2 on GPCRs and non-GPCRs and possible use as a drug target (Review)". International Journal of Molecular Medicine. 38 (4): 987–94. doi:10.3892/ijmm.2016.2720. PMID 27573285. 
  2. ^ a b Yamamoto H, Higa-Nakamine S, Noguchi N, Maeda N, Kondo Y, Toku S, Kukita I, Sugahara K (2014). "Desensitization by different strategies of epidermal growth factor receptor and ErbB4". Journal of Pharmacological Sciences. 124 (3): 287–93. PMID 24553453. 
  3. ^ Kelly E, Bailey CP, Henderson G (2008). "Agonist-selective mechanisms of GPCR desensitization". British Journal of Pharmacology. 153 Suppl 1: S379–88. doi:10.1038/sj.bjp.0707604. PMC 2268061Freely accessible. PMID 18059321. 
  4. ^ "heterologous desensitization". modofacto.com. Retrieved 2011-04-03. 
  5. ^ Métayé T, Gibelin H, Perdrisot R, Kraimps JL (2005). "Pathophysiological roles of G-protein-coupled receptor kinases". Cellular Signalling. 17 (8): 917–28. doi:10.1016/j.cellsig.2005.01.002. PMID 15894165. 
  6. ^ Zeitz C, Robson AG, Audo I (2015). "Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms". Progress in Retinal and Eye Research. 45: 58–110. doi:10.1016/j.preteyeres.2014.09.001. PMID 25307992.