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PMID: 2468163 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 86 ·No. 8 ·1989-04-00 ·Pages 2938-42

Heuschneider G, Schwartz RD

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.

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
Chemicals
Chloride Channels Chlorides Membrane Proteins Colforsin Muscimol gamma-Aminobutyric Acid Bucladesine Cyclic AMP 1-Methyl-3-isobutylxanthine
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Heuschneider G
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
Schwartz R D
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.86.8.2938
Published
1989-04-00
Pages
2938-42
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC287035
Subset
IM
Grants
NINDS NIH HHS · NS 24577 · United States
External Links
PubMed source DOI: 10.1073/pnas.86.8.2938 PMC Full Text View journal details
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