Adenylate cyclase supersensitivity: a general means of cellular adaptation to inhibitory agonists?

doi:10.1016/0165-6147(87)90124-6

Trends in Pharmacological Sciences

Volume 8, Issue 8, August 1987, Pages 308-311

https://doi.org/10.1016/0165-6147(87)90124-6 Get rights and content

Abstract

Chronic treatment of cultured nerve cells with drugs such as morphine which inhibit adenylate cyclase activity are well known to induce an enhanced activity of the enzyme that is found after withdrawal of the inhibitory drug. This phenomenon of supersensitive adenylate cyclase activity has been proposed to represent a cellular model for drug addiction. John Thomas and Brian Hoffman describe recent observations that this change in adenylate cyclase activity occurs in a wide variety of other types of cultured cells. The effect also appears to be induced in adipocytes by in-vivo treatment with inhibitory drugs. Induction of both the supersensitive adenylate cyclase activity in nerve cells and a physiological hallmark of drug addiction in animals appears to involve a pertussis toxin-sensitive G protein. Although there may be important analogies between inhibitor-induced changes in adenylate cyclase activity and drug addiction, the phenomenon of super-sensitive adenylate cyclase can be considered a more general cellular adaptation to chronic inhibition of the enzyme.

References (33)

J. Traber et al.
Life Sci.
(1975)
M. Brandt et al.
FEBS Lett.
(1976)
S.L. Sabol et al.
J. Biol. Chem.
(1979)
M. Wollemann
Prog. Neurobiol.
(1981)
K. Kuriyama
Trends Pharmacol. Sci.
(1982)
M. Wuster et al.
Life Sci.
(1983)
M. Wuster et al.
Trends Pharmacol. Sci.
(1985)
W.J. Parsons et al.
J. Biol. Chem.
(1987)
W.J. Northam et al.
eur. j. Pharmacol.
(1985)
D.A. Green et al.
Life Sci.
(1981)

H. Kurose et al.

J. Biol. Chem.

(1983)

P.Y. Law et al.

J. Biol. Chem.

(1985)

S.K. Sharma et al.

A. Lampert et al.

B. Hamprecht

G.C. Resenfeld et al.

Adv. Biochem. Psychopharmacol.

(1979)

Cited by (87)

Effects of long-term active immunization with the second extracellular loop of human β<inf>1</inf>- or β<inf>3</inf>-adrenoceptors in thoracic aorta and mesenteric arteries in Lewis rats
2016, Vascular Pharmacology
Citation Excerpt :
In agreement with this contention, the immunofluorescence assay and RT-qPCR revealed a slight although not significant down-regulation of β1-AR, β2-AR expression and mRNA in TA. In the current state of knowledge on this subject, it is recognized that the chronic stimulation of the receptor producing a high increase of cAMP is known to induce an excessive desensitization of both β1-AR and β2-AR [34,35]. The down-regulation of β-AR was already reported in TA of rats, which developed heart failure 6 weeks after myocardial infarction [36].
To evaluate whether active immunization producing β₁- or β₃-antibodies (β₁-ABs and β₃-ABs) detected in sera of patients with dilated cardiomyopathies has deleterious effects on vascular reactivity in Lewis rat thoracic aorta (TA) and small mesenteric arteries (SMA).
Lewis rats were immunized for 6 months with peptidic sequences corresponding to the second extracellular loop of β₁- and β₃-adrenoceptors (ARs). During the immunization, systolic blood pressure (SBP) was monitored using the tail cuff method. The vascular reactivity of immunized rats was assessed by ex vivo studies on SMA and TA using various β-AR agonists, phenylephrine and KCl.
The immunizations producing functional β₁-ABs and β₃-ABs did not affect the SBP. However, in TA from β₁-AR-immunized rats, the relaxations mediated by dobutamine and salbutamol were significantly impaired in comparison with adjuvant rats whereas nebivolol-induced relaxation was not modified. Moreover, phenylephrine and KCl-mediated contractions were enhanced in these rats. In contrast, immunization with β₃-AR peptide led to the increase of relaxations induced by dobutamine in TA but did not change those induced by salbutamol and nebivolol. Surprisingly, in SMA from both rats immunized with β₁- or β₃-peptides, relaxations induced by the various β-agonists were not changed whereas phenylephrine and KCl-mediated contractions were impaired.
Our study shows that β₁- and β₃-ABs can affect vascular reactivity. β₁-ABs would have a pathogenic action whereas β₃-ABs would have a beneficial effect on aorta reactivity.
Inhibition of heat shock protein 90 attenuates adenylate cyclase sensitization after chronic morphine treatment
2010, Biochemical and Biophysical Research Communications
Citation Excerpt :
One of the biochemical changes during chronic opioid treatment is a significant increase in adenylate cyclase activities stimulated by forskolin or Gs protein-coupled receptor [2,3]. This enhanced responsiveness, known as adenylate cyclase superactivation, eventually counteracts the acute effect of the Gi/o-coupled opioid receptor in inhibiting adenylate cyclase [2–5]. Of three opioid receptor subtypes, μ-opioid receptor (MOR) is the primary target for morphine analgesia.
Cellular adaptations to chronic opioid treatment result in enhanced responsiveness of adenylate cyclase and an increase in forskolin- or agonist-stimulated cAMP production. It is, however, not known whether chaperone molecules such as heat shock proteins contribute to this adenylate cyclase sensitization. Here, we report that treatment of cells with geldanamycin, an inhibitor of heat shock protein 90 (Hsp90), led to effective attenuation of morphine-induced adenylate cyclase sensitization. In SK-N-SH human neuroblastoma cells, morphine significantly increased RNA transcript and protein levels of type I adenylate cyclase, leading to sensitization. Whole-genome tiling array analysis revealed that cAMP response element-binding protein, an important mediator for cellular adaptation to morphine, associated with the proximal promoter of Hsp90AB1 not only in SK-N-SH cells but also in rat PC12 and human embryonic kidney cells. Hsp90AB1 transcript and protein levels increased significantly during morphine treatment, and co-application of geldanamycin (0.1–10 nM) effectively suppressed the increase in forskolin-activated adenylate cyclase activation by 56%. Type I adenylate cyclase, but not Hsp90AB1, underwent significant degradation during geldanamycin treatment. These results indicate that Hsp90 is a new pharmacological target for the suppression of adenylate cyclase sensitization induced by chronic morphine treatment.
Comparison of agmatine with moxonidine and rilmenidine in morphine dependence in vitro: Role of imidazoline I<inf>1</inf> receptors
2009, European Journal of Pharmacology
Moxonidine and rilmenidine are classical imidazoline I₁ receptor agonists, and used as anti-hypertension drugs in clinical practice. Agmatine is an imidazoline I₁ receptor endogenous ligand as well as its agonist, but more and more evidences suggest it has no influence on blood pressure. In the present study we compared the effects of moxonidine, rilmenidine and agmatine in the development of morphine dependence, and investigated the role of imidazoline I₁ receptor in the effects of these agents. Chinese hamster ovary cells co-expressing μ opioid receptor and imidazoline receptor antisera-selected protein (IRAS), the strong candidate for imidazoline I₁ receptor, were used as the cell line. cAMP overshoot, which represents an opioid dependent state in vitro, was measured to study the effects on morphine dependence. siRNA against IRAS was carried out to investigate the role of imidazoline I₁ receptor. Moxonidine and rilmenidine (0.01–10 µM) were ineffective on cAMP level in the cells when given alone, and failed to inhibit chronic morphine exposure, naloxone-precipitated cAMP overshoot when co-pretreated with morphine. Agmatine (0.01–10 µM) by itself was ineffective but co-pretreated with morphine concentration-dependently inhibited chronic morphine exposure, naloxone-precipitated cAMP overshoot in the cells. Furthermore, we found that the inhibitory effect of agmatine (100 nM and 1 µM) on cAMP overshoot was significantly reduced by siRNA against IRAS. This study indicates that agmatine can inhibit the development of morphine dependence in vitro, whereas moxonidine and rilmenidine have no the effect. Imidazoline I₁ receptor plays an important role in agmatine inhibiting morphine dependence.
Presynaptic inhibition of spontaneous acetylcholine release mediated by P2Y receptors at the mouse neuromuscular junction
2006, Neuroscience
Citation Excerpt :
Metabotropic P2Y receptors are coupled to second messenger pathways via either Gq/11 or Gi/o proteins (Filippov et al., 1998; Ralevic and Burnstock, 1998; Torres et al., 2002). In order to establish whether the presynaptic inhibitory action of βγ-imido ATP in mice diaphragm muscles was due to the activation of P2Y receptors coupled to Gi/o proteins, we investigated the effect of PTX (inactivates Gi/o through ADP ribosylation, Gilman, 1984; Thomas and Hoffman, 1987; Watts, 2002) and NEM (uncouple G protein from several receptors, Wu et al., 1992; Shapiro et al., 1994; Yeon et al., 2004). Diaphragms incubated in PTX (2 μM ml−1) for 12–14 h prevented the βγ-imido ATP-mediated reduction in MEPP frequency (12–14 h PTX 101.5±1.9% of control values; 12–14 h PTX+βγ-imido ATP 102.8±1.6%, n=4, Fig. 4A).
At the neuromuscular junction, ATP is co-released with the neurotransmitter acetylcholine (ACh) and once in the synaptic space, it is degraded to the presynaptically active metabolite adenosine. Intracellular recordings were performed on diaphragm fibers of CF1 mice to determine the action of extracellular ATP (100 μM) and the slowly hydrolysable ATP analog 5′-adenylylimidodiphosphate lithium (βγ-imido ATP) (30 μM) on miniature end-plate potential (MEPP) frequency. We found that application of ATP and βγ-imido ATP decreased spontaneous secretion by 45.3% and 55.9% respectively. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A₁ adenosine receptor antagonist and α,β-methylene ADP sodium salt (αβ-MeADP), which is an inhibitor of ecto-5′-nucleotidase, did not prevent the inhibitory effect of ATP, demonstrating that the nucleotide is able to modulate spontaneous ACh release through a mechanism independent of the action of adenosine. Blockade of Ca²⁺ channels by both, Cd²⁺ or the combined application of nitrendipine and ω-conotoxin GVIA (ω-CgTx) (L-type and N-type Ca²⁺ channel antagonists, respectively) prevented the effect of βγ-imido ATP, indicating that the nucleotide modulates Ca²⁺ influx through the voltage-dependent Ca²⁺ channels related to spontaneous secretion. βγ-Imido ATP-induced modulation was antagonized by the non-specific P2 receptor antagonist suramin and the P2Y receptor antagonist 1-amino-4-[[4-[[4-chloro-6-[[3(or4)-sulfophenyl] amino]-1,3,5-triazin-2-yl]amino]-3-sulfophenyl] amino]-9,10-dihydro-9,10-dioxo-2-anthracenesulfonic acid (reactive blue-2), but not by pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt (PPADS), which has a preferential antagonist effect on P2X receptors. Pertussis toxin and N-ethylmaleimide (NEM), which are blockers of G_i/o proteins, prevented the action of the nucleotide, suggesting that the effect is mediated by P2Y receptors coupled to G_i/o proteins. The protein kinase C (PKC) antagonist chelerythrine and the calmodulin antagonist N-(6-aminohexil)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) occluded the effect of βγ-imido ATP, while the protein kinase A (PKA) antagonist KT-5720 and the inhibitor of the calcium/calmodulin-dependent protein kinase II (CAMKII) KN-62 failed to do so. βγ-Imido ATP did not affect 10, 15 and 20 mM K⁺-evoked release and application of reactive blue-2 before incubation in high K⁺ induced a higher asynchronous secretion. Thus, our results show that at mammalian neuromuscular junctions, ATP induces presynaptic inhibition of spontaneous ACh release due to the modulation of Ca²⁺ channels related to tonic secretion through the activation of P2Y receptors coupled to G_i/o proteins. We also demonstrated that at increasing degrees of membrane depolarization evoked by K⁺, endogenously released ATP induces presynaptic inhibition as a means of preventing excessive neurotransmitter secretion.
Sensitization of adenylate cyclase by Gα<inf>i/o</inf>-coupled receptors
2005, Pharmacology and Therapeutics
Activation of receptors coupled to inhibitory G proteins (Gα_i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Gα_i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated. This heterologous sensitization of cyclic AMP signaling, also called superactivation or supersensitization, likely represents a cellular adaptive response, a mechanism by which the cell compensates for chronic inhibitory input. Recent advances in our knowledge of G protein-mediated signaling, regulation of adenylate cyclase, and other cellular signaling mechanisms have extensively increased our insight into the mechanisms and significance of this phenomenon. In particular, recent evidence points to the Gα_s–adenylate cyclase interface as a locus for the expression of the sensitized adenylate cyclase response, and to isoform-specific phosphorylation of adenylate cyclase as one mechanism that can produce sensitization. Gα_i/o-coupled receptor-induced heterologous sensitization may contribute to enhanced Gα_s-coupled receptor signaling following neurotransmitter elevations induced by the administration of drugs of abuse and during other types of neuronal function or dysfunction. This review will focus on recent advances in our understanding of signaling pathways that are involved in sensitization and describe the potential role of sensitization in neuronal function.
Effect of chronic treatment of ohmefentanyl stereoisomers on cyclic AMP formation in Sf9 insect cells expressing human μ-opioid receptors
2004, Life Sciences
The binding affinity of ohmefentanyl stereoisomers for μ-opioid receptors and the effect of chronic ohmefentanyl stereoisomers pretreatments on intracellular cAMP formation were investigated in Sf9 insect cells expressing human μ-opioid receptors (Sf9-μ cells). Competitive assay of [³H]ohmefentanyl binding revealed that these isomers had high affinity for μ-opioid receptors in Sf9-μ cells. Isomer F9204 had the highest affinity for μ-opioid receptors with the K_i value of 1.66 ± 0.28 nM. After pretreated Sf9-μ cells with increasing concentrations of these isomers for 6 h, addition of naloxone (1 μM) precipitated an overshoot of foskolin-stimulated cAMP accumulation. The ability of these isomers to induce cAMP overshoot differed greatly with the order of F9202 > F9205 > F9208 > F9206 > F9204 > F9207. Of these isomers, F9202 was 2.7-fold less potent than F9204 in receptor binding affinity, but 71.5-fold more potent in ability to induce cAMP overshoot. These results suggested that there was a significant stereo-structural difference among ohmefentanyl stereoisomers in ability to induce naloxone-precipitated cAMP overshoot in Sf9-μ cells.

View all citing articles on Scopus

View full text

Trends in Pharmacological Sciences

Adenylate cyclase supersensitivity: a general means of cellular adaptation to inhibitory agonists?

Abstract

Life Sci.

FEBS Lett.

J. Biol. Chem.

Prog. Neurobiol.

Trends Pharmacol. Sci.

Life Sci.

Trends Pharmacol. Sci.

J. Biol. Chem.

eur. j. Pharmacol.

Life Sci.

J. Biol. Chem.

J. Biol. Chem.

Adv. Biochem. Psychopharmacol.