Homologous desensitization

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General pathways for GPCR homologous desensitization Homologous Desensitization Pathways.jpg
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]

Contents

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]

Mechanisms

For GPCRs generally, each mechanism of homologous desensitization begins with receptor phosphorylation by an associated G protein-coupled receptor kinase (GRK). GRKs selectively modify activated receptors such that no heterogeneous desensitization will occur. This phosphorylation then acts to recruit other proteins, such as arrestins, that participate in one or more of the following mechanisms.

Receptor uncoupling

Receptor uncoupling/phosphorylation is the most rapid form of desensitization that happens within a cell, as its effects are seen within seconds to minutes of agonist application. [5] The ß2 adrenergic receptor was the first to have its desensitization studied and characterized. The mechanism of desensitization involves the action of a specific GRK, denoted ßARK, and also ß-arrestins. The ß-arrestins show high affinity for receptors that are both phosphorylated and activated, but are still able to bind non-phosphorylated receptors with a lower affinity. Additionally, ß-arrestins are better at inactivating ßARK-phosphorylated receptors rather than protein kinase A-phosphorylated receptors, which suggests that the arrestins preferentially mediate homologous desensitization. [6]

The mechanism of homologous desensitization for the β2 receptor is as follows:

  1. Agonist binds and activates the receptor, which changes to an active conformational state.
  2. Beta adrenergic receptor kinase (βARK), a cytoplasmic kinase is activated and phosphorylates the C-terminus of the β2 receptor.
  3. This phosphorylation increases the affinity of β-arrestin for the receptor, resulting in uncoupling of the α subunit of the heterotrimeric G-protein from the receptor, producing desensitization.[ citation needed ]

Endocytosis

In contrast to receptor uncoupling, endocytosis can occur through multiple pathways. GPCR endocytosis has been shown to be either dependent or independent of arrestin activity, depending on the cell type used in the experiment; however, the former is more common. Furthermore, the same receptor expressed in two distinct cell types can be endocytosed through different mechanisms due to differences in GRK and arrestin expression: either through clathrin-coated vesicles or caveolae. [4] In general, receptor sequestration preferentially affects receptors that are both activated and phosphorylated, but the phosphorylation is not always a necessary component of endocytosis. After being sequestered, the affected receptors can either be degraded by lysosomes or reinserted into the plasma membrane, which is called receptor recycling. [5]

Post-translational modification also affects receptor endocytosis. For example, different glycosylations on the exterior N-terminus of dopamine receptors D2 and D3 were associated with specific endocytotic pathways. Additionally, palmitoylation, which primarily mediates receptor localization within the membrane, can also affect endocytosis. It is required for the endocytosis of thyrotropin-releasing hormone and D3 receptors, and it is inhibitory for leutinizing hormone and vasopressin receptor 1A receptors. It has been shown to have no effect on adrenergic receptors (specifically ß2 and α1). [3]

Related Research Articles

G protein-coupled receptor Class of cell surface receptors coupled to G-Protein associated intracelular signaling

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 proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. Ligands can bind either to extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.

Rod cell Photoreceptor cells that can function in lower light better than cone cells

Rod cells are photoreceptor cells in the retina of the eye that can function in lower light better than the other type of visual photoreceptor, cone cells. Rods are usually found concentrated at the outer edges of the retina and are used in peripheral vision. On average, there are approximately 92 million rod cells in the human retina. Rod cells are more sensitive than cone cells and are almost entirely responsible for night vision. However, rods have little role in color vision, which is the main reason why colors are much less apparent in dim light.

Beta-2 adrenergic receptor Mammalian protein found in Homo sapiens

The beta-2 adrenergic receptor, also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine (adrenaline), a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulation through trimeric Gs proteins, increased cAMP, and downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation.

Arrestin Family of proteins

Arrestins are a small family of proteins important for regulating signal transduction at G protein-coupled receptors. Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of G protein-coupled receptors (GPCRs) in the visual rhodopsin system by Hermann Kühn, Scott Hall, and Ursula Wilden and in the β-adrenergic system by Martin J. Lohse and co-workers.

G protein-coupled receptor kinase

G protein-coupled receptor kinases are a family of protein kinases within the AGC group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways.

Follicle-stimulating hormone receptor Protein-coding gene in the species Homo sapiens

The follicle-stimulating hormone receptor or FSH receptor (FSHR) is a transmembrane receptor that interacts with the follicle-stimulating hormone (FSH) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning of FSH. FSHRs are found in the ovary, testis, and uterus.

G protein-coupled receptor kinase 2 Enzyme

G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ADRBK1 gene. GRK2 was initially called Beta-adrenergic receptor kinase, and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK3(βARK2).

Rhodopsin kinase is a serine/threonine-specific protein kinase involved in phototransduction. This enzyme catalyses the following chemical reaction:

Arrestin beta 2

Beta-arrestin-2, also known as arrestin beta-2, is an intracellular protein that in humans is encoded by the ARRB2 gene.

Prostaglandin DP<sub>2</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene and GPR44. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with and respond to various prostaglandins. DP2 along with Prostaglandin DP1 receptor are receptors for prostaglandin D2 (PGD2). Activation of DP2 by PGD2 or other cognate receptor ligands has been associated with certain physiological and pathological responses, particularly those associated with allergy and inflammation, in animal models and certain human diseases.

Arrestin beta 1

Arrestin, beta 1, also known as ARRB1, is a protein which in humans is encoded by the ARRB1 gene.

GRK6

This gene encodes a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinase family, and is most highly similar to GRK4 and GRK5. The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.

GRK5

G protein-coupled receptor kinase 5 is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases, and is most highly similar to GRK4 and GRK6. The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.

SAG (gene)

S-arrestin is a protein that in humans is encoded by the SAG gene.

GRK4 Protein-coding gene in the species Homo sapiens

G protein-coupled receptor kinase 4 (GRK4) is an enzyme that in humans is encoded by the GRK4 gene.

G beta-gamma complex

The G beta-gamma complex (Gβγ) is a tightly bound dimeric protein complex, composed of one Gβ and one Gγ subunit, and is a component of heterotrimeric G proteins. Heterotrimeric G proteins, also called guanosine nucleotide-binding proteins, consist of three subunits, called alpha, beta, and gamma subunits, or Gα, Gβ, and Gγ. When a G protein-coupled receptor (GPCR) is activated, Gα dissociates from Gβγ, allowing both subunits to perform their respective downstream signaling effects. One of the major functions of Gβγ is the inhibition of the Gα subunit.

G-protein-coupled receptor kinase 7 is a serine/threonine-specific protein kinase involved in phototransduction. This enzyme catalyses the phosphorylation of cone (color) photopsins in retinal cones during high acuity color vision primarily in the fovea.

Heterologous 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 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.

G protein-coupled receptor kinase 3

G-protein-coupled receptor kinase 3 (GRK3) is an enzyme that in humans is encoded by the ADRBK2 gene. GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK2.

Alpha Arrestin

The arrestin family of proteins is subdivided into α-arrestins (also referred to as arrestin-related trafficking adaptors or arrestin-like yeast proteins in yeast or ARRDCs in mammals, β-arrestins and Vps26-like arrestins proteins. The α-Arrestins are an ancestral branch of the larger arrestin family of proteins and they are conserved across eukaryotes but are best characterized in the budding yeast Saccharomyces cerevisiae; to-date there are 6 α-arrestins identified in mammalian cells and 14 α-arrestins identified in the budding yeast Saccharomyces cerevisiae. The yeast α-arrestin family comprises Ldb19/Art1, Ecm21/Art2, Aly1/Art6, Aly2/Art3, Rod1/Art4, Rog3/Art7, Art5, Csr2/Art8, Rim8/Art9, Art10, Bul1, Bul2, Bul3 and Spo23. The best characterized α-arrestin function to date is their endocytic regulation of plasma membrane proteins, including G-protein coupled receptors and nutrient transporters. α-Arrestins control endocytosis of these membrane proteins in response to cellular stressors, including nutrient or metal ion excess.

References

  1. ↑ "homologous desensitization". Medical Dictionary. Drugs.com. Retrieved 18 May 2011.
  2. ↑ 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.
  3. 1 2 3 Zhang, 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.
  4. 1 2 Gergs, Ulrich; Fritsche, Julia; Fabian, Stephanie; Christ, Josepha; Neumann, Joachim (2017). "Desensitization of the human 5-HT4 receptor in isolated atria of transgenic mice". Naunyn-Schmiedeberg's Archives of Pharmacology. 390 (10): 987–996. doi:10.1007/s00210-017-1403-2. PMID   28689254.
  5. 1 2 3 4 Ferguson, 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.
  6. 1 2 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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