Question

Cell Biology Short Answer Question: Describe the various molecular mechanisms for receptor desensitization. How can a receptor be reset to its original sensitized state?

Answer 1

Receptor desensitization refers to the decreased responsiveness that occurs with repeated or chronic exposure to agonist and is a general feature of most signaling membrane receptors. Mechanistically, desensitization can be divided into receptor uncoupling from downstream signal transduction elements by phosphorylation and reversible binding of the protein arrestin; receptor internalization by endocytosis; and receptor down-regulation (i.e., reduction in total receptor number) by a combination of increased degradation and reduced synthesis.

1.Beta 2 agonist and antagonist:desensitization of the beta2-adrenoceptor in airway smooth muscle is self-limited such that responsiveness is only partially impaired; this differs from the profound desensitization that can occur in other biologic systems. Some aspects of beta2-adrenoceptor desensitization depend on agonist occupancy (“homologous desensitization”), whereas other aspects do not (“heterologous desensitization”). Homologous desensitization is sensitive to agonist efficacy such that agonists of higher intrinsic efficacy may induce more desensitization.

2.Guanylyl Cyclase:

GC-A and GC-B

Receptor desensitization by posttranslational modification of the receptor molecule has been proposed for both GC-A and GC-B, where ANP and CNP desensitize GC-A and GC-B, respectively. Both GC-A and GC-B are phosphorylated on specific serine and threonine residues in the KHD, and ligand-induced desensitization is associated with dephosphorylation of the phosphoserine and phosphothreonine residues.

Desensitization of GC-A and GC-B by signaling molecules other than ligands has been reported as well. This type of desensitization can also generally be correlated with dephosphorylation of phosphoserine and phosphothreonine residues. Angiotensin II (AII) and arginine vasopressin can attenuate ANP-induced cGMP generation in rat vascular SMCs, glomerular mesangial cells, and adrenocortical carcinoma cell lines. Endothelins (ETs) can attenuate ANP- and CNP-induced cGMP generations in rat vascular SMCs and murine astrocytes, respectively. AII and ETs appear to cause this desensitization through stimulation of PKC.

3.arrestins:

Arrestins in GPCR Desensitization

Receptor desensitization represents an important physiological process that prevents GPCRs from overstimulation due to prolonged agonist exposure by signal attenuation or termination.2,3The classical model of GPCR desensitization involves three processes: (1) receptor phosphorylation and subsequent uncoupling of the receptor from its cognate G protein, (2) receptor sequestration (internalization) to intracellular compartments, and (3) downregulation.

4. Ghrelin Receptors:

Internalization of ghrelin receptor

In the normal healthy organism, ghrelin receptor desensitization and endocytosis govern the ability of cells to respond to ghrelin, thereby regulating intracellular signaling to avoid permanent stimulation of target cells. Receptor resensitization determines the frequency of the response to ghrelin. In addition, the composition of the plasma membrane affects the responsiveness of cells to metabolically important hormones such as ghrelin and insulin. Deficiencies in this attenuation system may lead to an uncontrolled or defective stimulation of target cells, alteration of their intracellular signaling, and subsequent pathological changes.