166954

cAMP and forskolin decrease gamma-aminobutyric acid-gated chloride flux in rat brain synaptoneurosomes.

Article date: 1989/4/1

PubMed ID: 166954

Journal name: Proceedings of the National Academy of Sciences of the United States of America (ISSN: 0027-8424)

ABSTRACT

The effects of the cyclic nucleotide cAMP on gamma-aminobutyric acid-gated chloride channel function were investigated. The membrane-permeant cAMP analog N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate inhibited muscimol-induced 36Cl- uptake into rat cerebral cortical synaptoneurosomes in a concentration-dependent manner (IC50 = 1.3 mM). The inhibition was due to a decrease in the maximal effect of muscimol, with no change in potency. Similar effects were observed with 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate, 8-bromoadenosine 3',5'-cyclic monophosphate, and the phosphodiesterase inhibitor isobutylmethylxanthine. The effect of endogenous cAMP accumulation on the gamma-aminobutyric acid-gated Cl- channel was studied with forskolin, an activator of adenylate cyclase. Under identical conditions, in the intact synaptoneurosomes, forskolin inhibited muscimol-induced 36Cl- uptake and generated cAMP with similar potencies (IC50 = 14.3 microM; EC50 = 6.2 microM, respectively). Surprisingly, 1,9-dideoxyforskolin, which does not activate adenylate cyclase, also inhibited the muscimol response, suggesting that forskolin and its lipophilic derivatives may interact with the Cl- channel directly. Indeed, forskolin inhibition of muscimol-induced 36Cl- uptake was extremely rapid (within 5 sec), preceding the accumulation of sufficient levels of cAMP. After 5 min, a slower phase of inhibition was seen, similar to the time course for cAMP accumulation. The data suggest that gamma-aminobutyric acid (GABAA) receptor function in brain can be regulated by cAMP-dependent phosphorylation.

Author List: Heuschneider G, Schwartz R D

Publication Types: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.

Substances mentioned in the article: Chloride Channels; Chlorides; Membrane Proteins; Colforsin; Muscimol; gamma-Aminobutyric Acid; Bucladesine; Cyclic AMP; 1-Methyl-3-isobutylxanthine;

Mesh terms: 1-Methyl-3-isobutylxanthine/pharmacology; Animals; Brain/physiology; Bucladesine/pharmacology; Chloride Channels; Chlorides/physiology; Colforsin/pharmacology; Cyclic AMP/physiology; In Vitro Techniques; Membrane Proteins/physiology; Muscimol/pharmacology; Rats; Synaptosomes; gamma-Aminobutyric Acid/physiology;

Citations: - 4394110

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