Gi down-regulation as a mechanism for heterologous desensitization in adipocytes.

Green, A; Milligan, Graeme; Dobias, Susan B.

doi:10.1016/s0021-9258(19)50719-0

Cited by 69 publications

(6 citation statements)

References 49 publications

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“…GC is not the only G-protein which has been noted to be downregulated by the maintained presence of an agonist for a relevant receptor. Members of the G, family [28,29] and Gq family [30,31] of G-proteins have been reported to be down-regulated in a similar manner to that reported herein. For the muscarinic Ml acetylcholine receptor when expressed in CHO cells, downregulation of the G-protein (Gq/Gll) [30,31] results from agonistinduced enhancement of G-protein turnover, with little or no contribution from transcriptional control [31].…”

Section: Discussionsupporting

confidence: 82%

“…It has been clearly observed that both ethanol [33]and prostanoid [8]induced down-regulation in NG108-15 cells results in the heterologous desensitization of receptor stimulation of adenylate cyclase. Furthermore, maintained exposure to certain, but not all, anti-lipolytic agents is able to produce down-regulation of each of Gil, Gi2 and G,3 in rat white adipocytes either in vivo [34] or when maintained in tissue culture [18,28]. Agents which cause down-regulation of the G-proteins produce heterologous desensitization of control of glycerol release, whereas agents which do not down-regulate the G-proteins produce only homologous desensitization [28].…”

Section: Discussionmentioning

confidence: 99%

“…Antiserum IM 1 was generated against amino acids [22][23][24][25][26][27][28][29][30][31][32][33][34][35] (NLKEDGISAAKDV) of forms of G.a. The specificities and characterization of these antisera have previously been fully described [15].…”

Section: Cell Growthmentioning

confidence: 99%

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Agonist regulation of cellular Gs α-subunit levels in neuroblastoma × glioma hybrid NG108-15 cells transfected to express different levels of the human β 2 adrenoceptor

Adie

Milligan

1994

Biochemical Journal

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Neuroblastoma x glioma hybrid NG108-15 cells endogenously express at least three receptors which activate adenylate cyclase via the intermediacy of the stimulatory G-protein, Gs. Sustained exposure of the cells to agonists at the IP prostanoid receptor results in a substantial decrease in cellular levels of the alpha-subunit of Gs (Gs alpha) [McKenzie and Milligan (1990) J. Biol. Chem. 265, 17084-17093; Adie, Mullaney, McKenzie and Milligan (1992) Biochem J. 285, 529-536]. By contrast, equivalent treatments of the cells with agonists at either the A2 adenosine receptor or the secretin receptor have no measurable effect on cellular amounts of Gs alpha. To examine whether this is a feature specific to the IP prostanoid receptor or is related to the level of expression of the individual receptors, NG108-15 cells were transfected with a construct containing a human beta 2-adrenoceptor cDNA under the control of the beta-actin promoter. Two clones of these cells were examined in detail, beta N22, which expressed some 4000 fmol/mg of membrane protein, and clone beta N17, which expressed approx. 300 fmol/mg of membrane protein of the receptor. Exposure of beta N22 cells to the beta-adrenergic agonist isoprenaline resulted maximally in some 55% decrease in membrane-associated levels of Gs alpha, without effect on membrane levels of Gi2 alpha, Gi3 alpha, G(o) alpha or Gq alpha/G11 alpha. Dose-response curves to isoprenaline in beta N22 cells indicated that half-maximal down-regulation of Gs alpha was produced by approx. 1 nM agonist. Equivalent exposure of beta N17 cells to isoprenaline did not significantly modify levels of any of the G-protein alpha subunits, including Gs alpha. In beta N22 cells the IP prostanoid receptor was expressed at similar levels to those in wild-type NG108-15 cells, and treatment with iloprost resulted in a similar down-regulation of cellular Gs alpha levels. Iloprost was also effective in causing down-regulation of Gs alpha levels in clone beta N17. Concurrent addition of both isoprenaline and iloprost to clone beta N22 resulted in less than additive down-regulation of Gs alpha. These results demonstrate that the phenomenon of agonist-induced specific G-protein down-regulation is determined by the levels of expression of the receptor.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Agonist regulation of cellular Gs α-subunit levels in neuroblastoma × glioma hybrid NG108-15 cells transfected to express different levels of the human β 2 adrenoceptor

Adie

Milligan

1994

Biochemical Journal

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“…On e pot ential mechani sm of heterologous desen sitization is that of regulation of G-protein function a nd expression, since changes at this level via one receptor would be expecte d to affect th e signa ling ca pacity of an y ot her receptor t hat utilizes t he pa rticula r G-protein to activ ate it s a ppropria te effector. Evidence in sUPPOJ't of thi s hypothesis has accumula te d over recent years, du e to th e availa bility of antisera capable of discriminating among th e multiple G-protein su bunits expressed in many cell types (11)(12)(13)33 ). In particular, man y st udies have demonstrated that chronic cellular expos ure to specific agoni sts results in a rapid down-regul ation of th e G-prote in which that receptor might be expecte d to activ a te up on agonis t occu pa ncy; these effects a re gene ra lly ind ependen t of second messen ger gene ration desp ite the requirem ent for receptor activa tion (33).…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, it has been suggested that chronic agonist exposure can result in the specific down-regulation of the G-protein with which a receptor preferentially couples. This phenomenon has been studied extensively in rat adipocytes both in the intact animal (11) and in primary adipocyte cultures (12,13) and suggests that chronic stimulation of the rat AlAR results in the heterologous desensitization of other anti-lipolytic hormone responses due to the down-regulation of G i proteins (13). These changes are not the result of reduced gene transcription, as mRNA levels for each of the three GiO'-subunits expressed in adipocytes are unaffected by agonist treatment (11).…”

mentioning

confidence: 99%

Differential Interaction with and Regulation of Multiple G-proteins by the Rat A3 Adenosine Receptor

Palmer

Gettys

Stiles

1995

Journal of Biological Chemistry

128

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Interaction of the rat A3 adenosine receptor (A3AR) with G-proteins has been assessed using a stably transfected Chinese hamster ovary cell system. The non-selective AR agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased the labeling of a 41-kDa membrane protein by 4-azidoanilido-[alpha-32P]guanosine 5'-triphosphate (AA-[32P]GTP), a photolabile GTP analogue. Subsequent immunoprecipitation of Gi alpha-subunits indicated that NECA stimulated incorporation of label into both Gi alpha-2 and Gi alpha-3. Additional experiments revealed an A3AR stimulation of label into Gq and/or G11 alpha-subunits, albeit to a lesser degree than that elicited by endogenous P2U purinergic receptors. No interaction with Gs could be detected. Sustained cellular exposure to NECA induced A3AR desensitization and specific down-regulation of Gi alpha-3 and G-protein beta-subunits without changing levels of Gi alpha-2, Gs alpha, or Gq+11 alpha-subunits. Therefore the A3AR can interact with Gi alpha-2, Gi alpha-3, and, to some extent, Gq-like proteins, but sustained agonist exposure down-regulates only one of the G-proteins with which it interacts. This is the first description of the differing specificities of A3AR/G-protein coupling versus down-regulation in situ and provides a potential mechanism by which the A3AR could elicit the heterologous desensitization of signaling events mediated by Gi3.

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Triacylglycerol Storage and Mobilization, Regulation of

Müller¹,

Petry²

2006

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Gi down-regulation as a mechanism for heterologous desensitization in adipocytes.

Cited by 69 publications

References 49 publications

Agonist regulation of cellular Gs α-subunit levels in neuroblastoma × glioma hybrid NG108-15 cells transfected to express different levels of the human β 2 adrenoceptor

Agonist regulation of cellular Gs α-subunit levels in neuroblastoma × glioma hybrid NG108-15 cells transfected to express different levels of the human β 2 adrenoceptor

Differential Interaction with and Regulation of Multiple G-proteins by the Rat A3 Adenosine Receptor

Triacylglycerol Storage and Mobilization, Regulation of

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