Postreceptor modulation of cAMP accumulation in rat brain particulate fraction after ischemia— Involvement of protein kinase C
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The brain cyclic AMP generation was studied in rats subjected to 15 min of cardiac arrest. We have used a particulate, synaptoneurosomal fraction to demonstrate the effect of ischemia in vivo on the responsiveness of adenylate cyclase (AC) system. It has been shown that, although there is a slight decrease in AC activity after ischemia, the in vitro fractions produce more cAMP in response to a variety of stimuli, suggesting an indirect, nonadenylate cyclase activation mechanism.
For elucidation of this mechanism we have probed phorbol-12,13-dibutyrate (PDBu) as a direct PKC activator, forskolin to activate the catalytic subunit of AC, and cholera toxin (CT) for stabilizing the active, GTP-bound form of stimulatory guanine nucleotide binding protein (Gs). All these postreceptor AC modulators as well as the receptor activators such as adenosine and α1-adrenergic agonists markedly enhanced cAMP production in the rat brain particulate fraction, although the postischemic hyperactive response to these stimuli was still present. However, when AC was stimulated by the combination of CT and PDBu, cAMP responses were identical in both control and postischemic fractions.
The data, taken together, support the hypothesis that ischemia increases cAMP accumulation by facilitating the postreceptor AC activation through a PKC-involving pathway and by promoting the stronger coupling of membrane AC receptors with G-protein.
Protein kinase C (PKC) activity during cerebral ischemia was also investigated. In contradistinction to our expectation PKC decreased significantly in the ischemic brain to 85% of the control activity in the cytosol and 72% in the membranes. However, in the incubated postischemic brain particulate fraction a relative increase in the membranebound form of the enzyme, from 30% for control to 53% for ischemia, was observed. This may suggest that ischemia-induced membrane changes could promote the enzyme translocation/activation during recovery, resulting in the sensitization of cAMP producing system.
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- Postreceptor modulation of cAMP accumulation in rat brain particulate fraction after ischemia— Involvement of protein kinase C
Molecular and Chemical Neuropathology
Volume 17, Issue 1 , pp 65-77
- Cover Date
- Print ISSN
- Humana Press
- Additional Links
- Protein kinase C
- cerebral ischemia
- cAMP accumulation
- postreceptor modulation
- Author Affiliations
- 1. Department of Neurochemistry, Medical Research Centre. Polish Academy of Sciences, Dworkowa 3, 00-784, Warsaw, Poland
- 2. Laboratory of Experimental Physiology and Resuscitation of the Organism, Academy of Medical Sciences of the USSR, USSR