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Opiate-induced adenylyl cyclase superactivation is isozyme-specific
T Avidor-Reiss1, I Nevo, D Saya
1Department of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot, Israel.
The Journal of Biological Chemistry
|February 21, 1997
Summary
Chronic activation of mu-opioid receptors leads to adenylyl cyclase superactivation in an isozyme-specific manner. This suggests specific adenylyl cyclase isozymes are involved in opioid tolerance and withdrawal.
Area of Science:
- Neuropharmacology
- Molecular Biology
- Cell Signaling
Background:
- Inhibitory Gi/o-coupled receptors acutely inhibit adenylyl cyclase.
- Chronic activation paradoxically increases cAMP via adenylyl cyclase superactivation.
- Mechanisms and specific adenylyl cyclase isozymes involved in superactivation remain largely unknown.
Purpose of the Study:
- To investigate the isozyme-specific effects of acute and chronic mu-opioid receptor activation on adenylyl cyclase activity.
- To identify adenylyl cyclase isozymes responsible for agonist-induced superactivation.
Main Methods:
- Transfection of specific adenylyl cyclase (AC) isozymes into COS-7 cells.
- Acute and chronic stimulation of mu-opioid receptors with agonists.
- Measurement of AC activity following receptor stimulation.
Main Results:
- Acute mu-opioid receptor activation differentially affected AC isozymes: inhibition of I, V, VI, VIII; stimulation of II, IV, VII; no effect on III.
- Chronic mu-opioid receptor activation induced superactivation of AC isozymes I, V, VI, and VIII.
- AC isozymes II, III, IV, and VII were not superactivated; some showed reduced activity after chronic exposure.
Conclusions:
- Adenylyl cyclase superactivation by chronic mu-opioid receptor activation is isozyme-specific.
- Specific AC isozymes (I, V, VI, VIII) mediate superactivation, while others (II, IV, VII) are downregulated.
- These findings implicate distinct adenylyl cyclase isozymes in the development of opioid tolerance and withdrawal phenomena.