When a receptor decreases its response to an agonist at high concentration
General pathways for GPCR homologous desensitization
Homologous desensitization occurs when a receptor decreases its response to an agonist at high concentration.[1] It is a process through which, after prolonged agonist exposure, the receptor is uncoupled from its signaling cascade and thus the cellular effect of receptor activation is attenuated.[2]
Homologous desensitization is distinguished from heterologous desensitization, a process in which repeated stimulation of a receptor by an agonist results in desensitization of the stimulated receptor as well as other, usually inactive, receptors on the same cell. They are sometimes denoted as agonist-dependent and agonist-independent desensitization respectively. While heterologous desensitization occurs rapidly at low agonist concentrations, homologous desensitization shows a dose dependent response and usually begins at significantly higher concentrations.[3][4]
Homologous desensitization serves as a mechanism for tachyphylaxis and helps organisms to maintain homeostasis. The process of homologous desensitization has been extensively studied utilizing G protein–coupled receptors (GPCRs).[3][5] While the different mechanisms for desensitization are still being characterized, there are currently four known mechanisms: uncoupling of receptors from associated G proteins, endocytosis, degradation, and downregulation. The degradation and downregulation of receptors is often also associated with drug tolerance since it has a longer onset, from hours to days.[6] It has been shown that these mechanisms can happen independently of one another, but that they also influence one another. In addition, the same receptor expressed in different cell types can be desensitized by different mechanisms.[5]
^"homologous desensitization". Medical Dictionary. Drugs.com. Retrieved 18 May 2011.
^Fehmann, HC; Habener, JF (Jun 1991). "Homologous desensitization of the insulinotropic glucagon-like peptide-I (7-37) receptor on insulinoma (HIT-T15) cells". Endocrinology. 128 (6): 2880–8. doi:10.1210/endo-128-6-2880. PMID 1645253.
^ abZhang, Xiaohan; Kim, Kyeong-Man (2017). "Multifactorial Regulation of G Protein-Coupled Receptor Endocytosis". Biomolecules & Therapeutics. 25 (1): 26–43. doi:10.4062/biomolther.2016.186. PMC 5207461. PMID 28035080.
^Cite error: The named reference :3 was invoked but never defined (see the help page).
^ abFerguson, Stephen S. G. (2001-03-01). "Evolving Concepts in G Protein-Coupled Receptor Endocytosis: The Role in Receptor Desensitization and Signaling". Pharmacological Reviews. 53 (1): 1–24. ISSN 0031-6997. PMID 11171937.
^Böhm, Stephan K.; Grady, Eileen F.; Bunnett, Nigel W. (1997-02-15). "Regulatory mechanisms that modulate signalling by G-protein-coupled receptors". Biochemical Journal. 322 (1): 1–18. doi:10.1042/bj3220001. ISSN 0264-6021. PMC 1218151. PMID 9078236.
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