Reduction in the stability of the GS-catalytic unit complex of adenylate cyclase in isoproterenol-induced heterologous desensitization

Yamashita, Atsushi; Kurokáwa, Tomonori; Y, Une; Ishibashi, Shun

doi:10.1016/0014-2999(89)90155-6

Cited by 9 publications

(2 citation statements)

References 17 publications

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“…With homologous desensitization, effects are restricted to ␤-AR signaling, typically through receptor phosphorylation by G protein-coupled receptor kinases; phosphorylation blocks the coupling of ␤-ARs to G proteins and enables the binding of ␤-arrestin, leading to receptor internalization and consequent downregulation (17,29). With heterologous desensitization, ␤-agonists attenuate the ability of other G protein-coupled receptors to initiate cell signaling; the underlying mechanisms entail phosphorylation of other receptors, G proteins, or AC, as well as alterations of the expression and/or activity of G proteins or AC itself (7,15,19,34,52).…”

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confidence: 99%

Are developing β-adrenoceptors able to desensitize? Acute and chronic effects of β-agonists in neonatal heart and liver

Auman

Seidler

Tate

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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During fetal and neonatal development, β-adrenergic receptors (β-ARs) appear to be resistant to desensitization by β-agonist drugs. To determine the mechanisms underlying the regulatory differences between adults and neonates, we administered isoproterenol, a mixed β1/β2-AR agonist, and terbutaline, a β2-selective agonist. Effects were examined in the ensuing 4 h after a single injection, or after the last of four daily injections. We prepared cell membranes from heart (predominantly β1-ARs) and liver (predominantly β2-ARs) and assessed signal transduction in the adenylyl cyclase (AC) pathway. In the first few hours after a single administration of isoproterenol to adult rats, cardiac β-ARs showed activation of G proteins (elevated AC response to forskolin) and desensitization of β-AR-mediated responses; after the fourth injection, heterologous desensitization emerged, characterized by a loss of signaling mediated either through β-ARs or glucagon receptors. Terbutaline evoked an increase in the forskolin response but no desensitization of receptor-mediated responses. When we gave the same treatments to neonatal rats, we observed cardiac G protein activation, but there was neither homologous nor heterologous desensitization of β-ARs or glucagon receptors. In the adult liver, isoproterenol and terbutaline both failed to evoke desensitization, regardless of whether the drugs were given once or for 4 days. In neonates, however, acute or chronic treatment elicited homologous desensitization of β-AR-mediated AC signaling, while sensitizing the response to glucagon. These results show that neonatal β-ARs are inherently capable of desensitization in some, but not all, cell types; cellular responses can be maintained through heterologous sensitization of signaling proteins downstream from the receptor. Differences from adult patterns of response are highly tissue selective and are likely to depend on ontogenetic differences in subtypes of β-ARs and AC.

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confidence: 99%

Are developing β-adrenoceptors able to desensitize? Acute and chronic effects of β-agonists in neonatal heart and liver

Auman

Seidler

Tate

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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“…We also found reduced AlF stimulation of AC activity in mononuclear leukocytes from the group DP-1 (Table 1), but the postreceptor stimulation of AC by GTPγS was unchanged in mononuclear leukocytes from DP-1 (Table 1). Studies using parallel AC activations by either guanine nucleotides (such as GTPγS) or AlF during heterologous desensitization have noted that heterologous desensitization is associated with significant decreases in AC activity by both guanine nucleotides and AlF (Garrity et al, 1983; Edwards et al, 1987; Jaschonek et al, 1988; Yamashita et al, 1989). Thus, our finding reduced AlF-stimulation in the absence of reductions during GTPγS stimulation in mononuclear leukocytes from the group DP-1, suggests that a mechanism other than heterologous desensitization accounts for our observations in this group of depressed patients.…”

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confidence: 99%

Increased Gsα within blood cell membrane lipid microdomains in some depressive disorders: An exploratory study

Mooney

Samson

McHale

et al. 2013

Journal of Psychiatric Research

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The stimulatory guanine nucleotide binding protein Gs couples many cellular receptors to adenylate cyclase, and the Gsα subunit activates all 9 isoforms of the adenylate cyclase catalytic unit to produce the enzyme product cyclicAMP or cAMP. In prefrontal cortex and cerebellum of unipolar depressive suicides, Rasenick and colleagues have found increased concentrations of Gsα in membrane lipid microdomains (Donati et al, 2008), where the ensconced Gsα is less likely to activate adenylate cyclase by receptor and postreceptor pathways (Allen et al, 2005(Allen et al, & 2009.We report that a group of 7 depressed patients (DP-1) had (1) reduced activation of platelet receptor-stimulated adenylate cyclase by both prostaglandins E2 and D2 compared to controls, and (2) reduced postreceptor stimulation of adenylate cyclase by aluminum fluoride ion in both platelets and mononuclear leukocytes when compared to both another group of depressed patients (DP-2, n=17) and to controls (n=21). Our observations in the blood cells of the group DP-1 support the findings of Donati et al (2008), and they reflect the importance of this interaction between the activated Gsα subunit and membrane lipid microdomains in the pathophysiology and treatment of some major depressive disorders.

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Multiple Pathways for Glucagon-Induced Heterologous Desensitization of Liver Adenylyl Cyclase

Premont

Iyengar

1990

Activation and Desensitization of Transducing Pathways

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Reduction in the stability of the GS-catalytic unit complex of adenylate cyclase in isoproterenol-induced heterologous desensitization

Cited by 9 publications

References 17 publications

Are developing β-adrenoceptors able to desensitize? Acute and chronic effects of β-agonists in neonatal heart and liver

Are developing β-adrenoceptors able to desensitize? Acute and chronic effects of β-agonists in neonatal heart and liver

Increased Gsα within blood cell membrane lipid microdomains in some depressive disorders: An exploratory study

Multiple Pathways for Glucagon-Induced Heterologous Desensitization of Liver Adenylyl Cyclase

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