Desensitization of the beta-adrenergic receptor of frog erythrocytes. Recovery and characterization of the down-regulated receptors in sequestered vesicles.

Stadel, Jeffrey M.; Strulovici, Berta; Nambi, Ponnal; Lavin, T N; Briggs, Margaret M.; Caron, Marc G.; Lefkowitz, Robert J.

doi:10.1016/s0021-9258(18)32825-4

Cited by 185 publications

(15 citation statements)

References 30 publications

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“…The traditional definition of G proteincoupled receptor "sequestration" represents the movement of the receptor into a cellular compartment which is accessible to hydrophobic, but not hydrophilic ligands (45). Cellular ffactionation studies have even correlated this with receptor localization in a vesicular compartment which may be distinct from the plasmalemma (40,41). This further emphasizes the need for a distinct terminology for the "insulation" which occurs at the level of the plasmalemma.…”

Section: Discussionmentioning

confidence: 99%

Insulation of a G protein-coupled receptor on the plasmalemmal surface of the pancreatic acinar cell.

Roettger

Rentsch

Hadac

et al. 1995

The Journal of Cell Biology

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Abstract. Receptor desensitization is a key process for the protection of the cell from continuous or repeated exposure to high concentrations of an agonist. Wellestablished mechanisms for desensitization of guanine nucleotide-binding protein (G protein)-coupled receptors include phosphorylation, sequestration/internalization, and down-regulation. In this work, we have examined some mechanisms for desensitization of the cholecystokinin (CCK) receptor which is native to the pancreatic acinar cell, and have found the predominant mechanism to be distinct from these recognized processes. Upon fluorescent agonist occupancy of the native receptor, it becomes "insulated" from the effects of acid washing and becomes immobilized on the surface of the plasma membrane in a time-and temperaturedependent manner. This localization was assessed by ultrastructural studies using a colloidal gold conjugate of CCK, and lateral mobility of the receptor was assessed using fluorescence recovery after photobleaching. Of note, recent application of the same morphologic techniques to a CCK receptor-bearing Chinese hamster ovary cell line demonstrated prominent internalization via the clathrin-dependent endocytic pathway, as well as entry into caveolae (Roettger, B. F., R. U. Rentsch, D. Pinon, E. Holicky, E. Hadac, J. M. Larkin, and L. J. . J. Cell Biol. 128: 1029-1041. These organelles are not observed to represent prominent compartments for the same receptor to traverse in the acinar cell, although fluorescent insulin is clearly internalized in these cells via receptor-mediated endocytosis. In this work, the rate of lateral mobility of the CCK receptor is observed to be similar in both cell types (1-3 x 10 -1° cm2/s), while the fate of the agonistoccupied receptor is quite distinct in each cell. This supports the unique nature of desensitization processes which occur in a cell-specific manner. A plasmalemmal site of insulation of this important receptor on the pancreatic acinar cell could be particularly effective to protect the cell from processes which might initiate pancreatitis, while providing for the rapid resensitization of this receptor to ensure appropriate pancreatic secretion to aid in nutrient assimilation for the organism.G JANINE nucleotide-binding protein (G protein) 1-coupled receptors represent the largest family of receptors recognized today. They reside within the plasmalemma in a conformation which incorporates seven transmembrane helices. Agonists approach their binding sites on such molecules from the extracellular aqueous milieu, and induce a presumed conformational change of the receptor which facilitates its association with G proteins on the cytosolic face of the plasmalemma. This ternary complex of agonist-receptor-G protein typically represents the high affinity state of the receptor and a critical step in stimulus-activity coupling. Thus, agonist access

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Section: Discussionmentioning

confidence: 99%

Insulation of a G protein-coupled receptor on the plasmalemmal surface of the pancreatic acinar cell.

Roettger

Rentsch

Hadac

et al. 1995

The Journal of Cell Biology

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“…A wide variety of factors regulate the concentration of these receptors (13,30). The concentration of receptors can be regulated by translocation of receptors from the plasma membrane to intracellular compartments (46) or by altering rates of synthesis or degradation. Steroid hormones regulate the number of �-adrenergic receptors on cells (see below; 12).…”

Section: Mechanisms Of �-Adrenergic Receptor Regulationmentioning

confidence: 99%

“…This observation has provided a basis for experimentally assessing the efficiency of coupling of receptors with N proteins under the influence of agonists (26,32,44,45). A variety of circumstances-for example desensitization (26,30,46) .-..…”

Section: Mechanisms Of �-Adrenergic Receptor Regulationmentioning

confidence: 99%

Regulation of Beta-Adrenergic Receptors by Steroid Hormones

Davies¹

1984

Annual Review of Physiology

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Adrenal steroid hormones and catecholamines play central roles both in main taining survival in times of stress and in regulating normal physiologic respon siveness. The interplay between these two hormonal systems is of great physiological importance. Whereas catecholamines exert highly specific effects on specific tissues, steroid hormones have rather broad effects upon many physiologic functions in many tissues. The general pattern observed is one of steroid hormone-induced refinement or regulation of catecholamine mediated processes. In this chapter we review what is known about the mechanisms by which adrenal steroid hormones regulate the action of the j3-adrenergic receptor-adenylate cyclase system. Effects on the a-adrenergic receptors and the effects of gonadal steroids are not addressed (13,29). PHYSIOLOGIC MANIFESTATIONS OF STEROID-INDUCED I3-ADRENERGIC RECEPTOR REGULATIONSteroid hormones enhance several j3-adrenergic actions at the tissue level. Myocardialj3l-adrenergic responses such as positive inotropism (3,25), posi-119

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“…The reason for this difference is not clear. A small amount of fluoride stimulation of adenylyl cyclase in "light" membranes containing d-adrenergic receptors has also been observed, although N proteins and catalytic subunits were not translocated into such fractions along with receptors (Stadel et al, 1983;Waldo et al, 1983). Welton et al (1977) demonstrated that active adenylyl cyclase and l25I-glucagon/receptor complexes could be solubilized from rat liver plasma membranes.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of such special treatment and after uncoupling, some /3-adrenergic receptors are translocated from plasma membranes to intracellular, light membranes (Waldo et al, 1983;Stadel et al, 1983), where only low-affinity receptors are found (Stadel et al, 1983;Toews et al, 1984). Such light membranes cannot be completely resolved from Golgi elements (galactosyl transferase activity) by centrifugation through sucrose density gradients (Waldo et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

Characterization of glucagon receptors in Golgi fractions of rat liver: evidence for receptors that are uncoupled from adenylyl cyclase

Lipson¹,

Cherksey²,

Donner³

1986

Biochemistry

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Glucagon receptors have been identified and characterized in intermediate (Gi) and heavy (Gh) Golgi fractions from rat liver. At saturation, plasma membranes bound 3500 fmol of hormone/mg of membrane protein, while Gi and Gh bound 24 and 60 fmol of 125I-glucagon/mg of protein, respectively. Half-maximal saturation of binding to plasma membranes, Gi, and Gh occurred at approximately 4, 10, and 20 nM 125I-glucagon, respectively. Trichloroacetic acid precipitation of intact, but not degraded, glucagon was used to correct binding isotherms for hormone degradation. After such correction, half-maximal saturation of binding to plasma membranes, Gi, and Gh was observed in the presence of approximately 2, 7, and 14 nM hormone, respectively. After 90 min of dissociation in the absence of guanosine 5'-triphosphate (GTP), 86% of 125I-glucagon remained bound to plasma membranes, whereas only 42% remained bound to Golgi membranes. GTP significantly increased the fraction of 125I-glucagon released from plasma membranes but only slightly augmented the dissociation of hormone from Golgi fractions. 125I-Glucagon/receptor complexes solubilized from plasma membranes fractionated by gel filtration as high molecular weight (Kav = 0.16), GTP-sensitive complexes and lower molecular weight (Kav = 0.46), GTP-insensitive complexes. 125I-Glucagon complexes solubilized from Golgi membranes fractionated almost exclusively as the lower molecular weight species. The lower affinity of Golgi than plasma membrane receptors for hormone, the ability of glucagon to stimulate plasma membrane, but not Golgi membrane, adenylyl cyclase, and the near absence of high molecular weight, GTP-sensitive complexes in solubilized Golgi membranes demonstrate that plasma membrane contamination of Golgi fractions cannot account for the 125I-glucagon binding.(ABSTRACT TRUNCATED AT 250 WORDS)

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Desensitization of the beta-adrenergic receptor of frog erythrocytes. Recovery and characterization of the down-regulated receptors in sequestered vesicles.

Cited by 185 publications

References 30 publications

Insulation of a G protein-coupled receptor on the plasmalemmal surface of the pancreatic acinar cell.

Insulation of a G protein-coupled receptor on the plasmalemmal surface of the pancreatic acinar cell.

Regulation of Beta-Adrenergic Receptors by Steroid Hormones

Characterization of glucagon receptors in Golgi fractions of rat liver: evidence for receptors that are uncoupled from adenylyl cyclase

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