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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Receptor desensitization is defined as a time-dependent diminished responsiveness to a bound agonist that affects the dynamics, plasticity, and the overall activity of a given receptor. Desensitization protects against receptor overstimulation and enables the integration of a biological signal through feedback from second messengers [37]. Therapeutically, however, desensitization is viewed as a considerable impediment because it ultimately limits the efficacy of some drugs. Two types of desensitization modes have been recognized: homologous and heterologous [7]. Homologous desensitization refers to loss of response to an agonist that acts upon a specific receptor subtype, whereas heterologous desensitization refers to diminished responsiveness to a ligand resulting from input by signaling component(s) downstream of the receptor [38].
An Investigation in Vitro of the Properties of the Individual Muscle Layers of the Rabbit Colon in an Induced Colitis.
Published in William J. Snape, Stephen M. Collins, Effects of Immune Cells and Inflammation on Smooth Muscle and Enteric Nerves, 2020
WH Percy, MB Burton, Y Jacobowitz, R Burakoff
By comparison, relatively little is known about the mechanisms underlying desensitization to arachidonic acid metabolites in any biological system. In the case of PGE1 it has been reported that for human astrocytoma cells and human fibroblasts desensitization results from an alteration in adenylate cyclase function35,36. In frog erythrocytes the desensitization-associated fall in PGEl-stimulated adenylate cyclase activity is coupled to a decrease in the number of cell surface PGE1 receptors37. Interestingly, in the guinea pig taenia caeci in vitro, exposure to a high concentration of 16,16 dimethyl-PGE2 causes desensitization of the PGE receptors mediating excitation, revealing a second, nqn-desensitized population of PGE receptors which mediate relaxation38. This is suggestive of a homologous desensitization, i.e. the desensitization is specific for pharmacologic agents activating one particular receptor type and does not occur at the level of some intracellular process which is common to several different types of receptor.
Supersensitivity and Desensitization
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
In homologous desensitization, only the responsiveness to the desensitizing agent is diminished and is usually specific for the receptor type in question. Heterologous desensitization is associated with a loss of responsiveness to a range of agents acting through the same second messenger pathway. The distinction is, however, not always clear since both types of desensitization may occur simultaneously (Harden 1983).
State-of-the-art beta-adrenoreceptor agonists for the treatment of asthma
Published in Expert Opinion on Pharmacotherapy, 2022
W. Tatiana Garzon-Siatoya, Ismael Carrillo-Martin, Sergio E Chiarella, Alexei Gonzalez-Estrada
In asthma, the inflammation-induced dysregulation of these tonic contractions, and the increased bulk of ASM in the remodeled airways, produce greater sensitivity and responsiveness to bronchoconstrictors. Furthermore, ASM relaxation may be hampered by the loss of functional β2-ARs and/or signaling in severe asthma. This could be the result of β2-ARs homologous desensitization caused by the recurrent use of large dosages of bronchodilator treatment or heterologous desensitization caused by uncontrolled inflammation [22].
Arrestin-3 differentially regulates platelet GPCR subsets
Published in Platelets, 2020
James L. Hutchinson, Xiaojuan Zhao, Rob Hill, Stuart J. Mundell
Interestingly, CRP-XL-induced GPVI responses were unaltered in arr3-/- mice. While not a GPCR, its heavy reliance on secondary mediators would suggest GPVI-induced activation might be altered. That it appears not to be could be explained by opposing signaling effects of arrestin-3 absence on ADP versus TP receptor ligands. Stimulation of TP receptors gave a unique response pattern as compared to ADP or thrombin. While the overall aggregation response to U46619 was enhanced in the arr3-/- mice, this was clearly driven by increased second-wave aggregation that is known to be ADP-dependent [18]. The evident defect in mutant calcium response suggests that signaling downstream of the TP receptor is regulated quite differently to that of P2Y receptors with respect to arrestin-3. It is interesting that Schaff et al. reported a mild aggregation defect in arr3-/- mice challenged with U46619 consistent with reduced receptor signaling [5]. The apparent second-wave dependence of the enhanced U46619 aggregation response, together with the 10-fold higher thrombin concentration required by Schaff et al. to elicit a robust aggregation response compared to the current study, is notable. The differences between the largely negative data of Schaff et al. and the present study may relate to differences in receptor/pathway sensitivity associated with platelet isolation technique. In addition to this apparent increase in receptor sensitivity in our study the employment of full dose–response curves may have afforded a greater detection window [6,19]. That aside, it remains unclear why the arrestin-3 sensitivity of TP receptor signaling differs from that of other major activatory platelet GPCRs. Differences between regulatory P2Y1 and P2Y12 phosphorylation pathways have already been noted [6]. Similar to P2Y1, homologous desensitization of platelet TP receptor reportedly occurs through PKC [20], while arrestin-3 mediated TP receptor internalization in HEK is selective for the TPβ, as opposed to the predominant platelet TPα, isoform [21]. Whether the kinase species involved in desensitization of a particular receptor also determines the role(s) of arrestins in platelet receptor regulation remains to be demonstrated. Also, the ability of arrestin-2 and −3 to compensate functionally for each other’s absence may well depend on both receptor and signaling context. Further studies using specific receptor inhibitors could address some of these questions. While knockout studies have previously shown a prothrombotic function for arrestin-2 downstream of PAR4-P2Y12 heterodimers, this paper presents novel evidence supporting a straightforward negative regulatory role for arrestin-3 downstream of a subset of activatory platelet GPCRs including the P2Y12R. This study demonstrates therefore for the first time that the ‘classical’ function of arrestins in limiting GPCR activation is relevant in platelets.