Involvement of Raf-1 in chronic δ-opioid receptor agonist-mediated adenylyl cyclase superactivation

Eva V. Varga; Marc Rubenzik; Vanessa Grife; Masano Sugiyama; Dagmar Stropova; William R. Roeske; Henry I. Yamamura

doi:10.1016/S0014-2999(02)02220-3

Involvement of Raf-1 in chronic δ-opioid receptor agonist-mediated adenylyl cyclase superactivation

Eva V. Varga, Marc Rubenzik, Vanessa Grife, Masano Sugiyama, Dagmar Stropova, William R. Roeske, Henry I. Yamamura

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Abstract

Chronic δ-opioid receptor agonist treatment of Chinese hamster ovary (CHO) cells stably expressing the human δ-opioid receptor (hDOR/CHO) leads to increased cAMP formation after the removal of the agonist (adenylyl cyclase superactivation). We have previously found that at the same time, chronic δ-opioid receptor agonist treatment augments phosphorylation of the adenylyl cyclase VI isoenzyme. Since phosphorylation of adenylyl cyclase VI by Raf-1 protein kinase was recently shown, we tested the role of Raf-1 in adenylyl cyclase superactivation in hDOR/CHO cells. We found that pretreatment of the cells with the selective Raf-1 inhibitor GW5074 (3-(3,5-dibromo-4-hydroxybenzylidene-5-iodo-1,3-dihydro-indol-2-one) (10 μM, 30 min) attenuates chronic deltorphin II-mediated increase in forskolin-stimulated cAMP formation by 40% (n=6, P<0.05). Better understanding of the molecular mechanism of adenylyl cyclase superactivation should aid in the development of analgesics that act longer and have fewer side effects.

Original language	English (US)
Pages (from-to)	101-102
Number of pages	2
Journal	European Journal of Pharmacology
Volume	451
Issue number	1
DOIs	https://doi.org/10.1016/S0014-2999(02)02220-3
State	Published - Sep 6 2002

Keywords

Adenylyl cyclase superactivation
Human
Raf-1
δ-Opioid receptor

ASJC Scopus subject areas

Pharmacology

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10.1016/S0014-2999(02)02220-3

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title = "Involvement of Raf-1 in chronic δ-opioid receptor agonist-mediated adenylyl cyclase superactivation",

abstract = "Chronic δ-opioid receptor agonist treatment of Chinese hamster ovary (CHO) cells stably expressing the human δ-opioid receptor (hDOR/CHO) leads to increased cAMP formation after the removal of the agonist (adenylyl cyclase superactivation). We have previously found that at the same time, chronic δ-opioid receptor agonist treatment augments phosphorylation of the adenylyl cyclase VI isoenzyme. Since phosphorylation of adenylyl cyclase VI by Raf-1 protein kinase was recently shown, we tested the role of Raf-1 in adenylyl cyclase superactivation in hDOR/CHO cells. We found that pretreatment of the cells with the selective Raf-1 inhibitor GW5074 (3-(3,5-dibromo-4-hydroxybenzylidene-5-iodo-1,3-dihydro-indol-2-one) (10 μM, 30 min) attenuates chronic deltorphin II-mediated increase in forskolin-stimulated cAMP formation by 40% (n=6, P<0.05). Better understanding of the molecular mechanism of adenylyl cyclase superactivation should aid in the development of analgesics that act longer and have fewer side effects.",

keywords = "Adenylyl cyclase superactivation, Human, Raf-1, δ-Opioid receptor",

author = "Varga, {Eva V.} and Marc Rubenzik and Vanessa Grife and Masano Sugiyama and Dagmar Stropova and Roeske, {William R.} and Yamamura, {Henry I.}",

note = "Funding Information: This work was supported in parts by grants from the Arizona Disease Control Research Commission and the National Institute of Health. We thank Michelle Thatcher for maintaining the hDOR/CHO cell culture.",

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AU - Varga, Eva V.

AU - Rubenzik, Marc

AU - Grife, Vanessa

AU - Sugiyama, Masano

AU - Stropova, Dagmar

AU - Roeske, William R.

AU - Yamamura, Henry I.

N1 - Funding Information: This work was supported in parts by grants from the Arizona Disease Control Research Commission and the National Institute of Health. We thank Michelle Thatcher for maintaining the hDOR/CHO cell culture.

PY - 2002/9/6

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N2 - Chronic δ-opioid receptor agonist treatment of Chinese hamster ovary (CHO) cells stably expressing the human δ-opioid receptor (hDOR/CHO) leads to increased cAMP formation after the removal of the agonist (adenylyl cyclase superactivation). We have previously found that at the same time, chronic δ-opioid receptor agonist treatment augments phosphorylation of the adenylyl cyclase VI isoenzyme. Since phosphorylation of adenylyl cyclase VI by Raf-1 protein kinase was recently shown, we tested the role of Raf-1 in adenylyl cyclase superactivation in hDOR/CHO cells. We found that pretreatment of the cells with the selective Raf-1 inhibitor GW5074 (3-(3,5-dibromo-4-hydroxybenzylidene-5-iodo-1,3-dihydro-indol-2-one) (10 μM, 30 min) attenuates chronic deltorphin II-mediated increase in forskolin-stimulated cAMP formation by 40% (n=6, P<0.05). Better understanding of the molecular mechanism of adenylyl cyclase superactivation should aid in the development of analgesics that act longer and have fewer side effects.

AB - Chronic δ-opioid receptor agonist treatment of Chinese hamster ovary (CHO) cells stably expressing the human δ-opioid receptor (hDOR/CHO) leads to increased cAMP formation after the removal of the agonist (adenylyl cyclase superactivation). We have previously found that at the same time, chronic δ-opioid receptor agonist treatment augments phosphorylation of the adenylyl cyclase VI isoenzyme. Since phosphorylation of adenylyl cyclase VI by Raf-1 protein kinase was recently shown, we tested the role of Raf-1 in adenylyl cyclase superactivation in hDOR/CHO cells. We found that pretreatment of the cells with the selective Raf-1 inhibitor GW5074 (3-(3,5-dibromo-4-hydroxybenzylidene-5-iodo-1,3-dihydro-indol-2-one) (10 μM, 30 min) attenuates chronic deltorphin II-mediated increase in forskolin-stimulated cAMP formation by 40% (n=6, P<0.05). Better understanding of the molecular mechanism of adenylyl cyclase superactivation should aid in the development of analgesics that act longer and have fewer side effects.

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Involvement of Raf-1 in chronic δ-opioid receptor agonist-mediated adenylyl cyclase superactivation

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