PMID- 2468163
OWN - NLM
STAT- MEDLINE
DCOM- 19890524
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 86
IP  - 8
DP  - 1989 Apr
TI  - cAMP and forskolin decrease gamma-aminobutyric acid-gated chloride flux in rat 
      brain synaptoneurosomes.
PG  - 2938-42
AB  - 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.
FAU - Heuschneider, G
AU  - Heuschneider G
AD  - Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
FAU - Schwartz, R D
AU  - Schwartz RD
LA  - eng
GR  - NS 24577/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Chloride Channels)
RN  - 0 (Chlorides)
RN  - 0 (Membrane Proteins)
RN  - 1F7A44V6OU (Colforsin)
RN  - 2763-96-4 (Muscimol)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - 63X7MBT2LQ (Bucladesine)
RN  - E0399OZS9N (Cyclic AMP)
RN  - TBT296U68M (1-Methyl-3-isobutylxanthine)
SB  - IM
MH  - 1-Methyl-3-isobutylxanthine/pharmacology
MH  - Animals
MH  - Brain/*physiology
MH  - Bucladesine/pharmacology
MH  - Chloride Channels
MH  - Chlorides/*physiology
MH  - Colforsin/*pharmacology
MH  - Cyclic AMP/*physiology
MH  - In Vitro Techniques
MH  - Membrane Proteins/*physiology
MH  - Muscimol/pharmacology
MH  - Rats
MH  - Synaptosomes
MH  - gamma-Aminobutyric Acid/*physiology
PMC - PMC287035
EDAT- 1989/04/01 00:00
MHDA- 1989/04/01 00:01
PMCR- 1989/10/01
CRDT- 1989/04/01 00:00
PHST- 1989/04/01 00:00 [pubmed]
PHST- 1989/04/01 00:01 [medline]
PHST- 1989/04/01 00:00 [entrez]
PHST- 1989/10/01 00:00 [pmc-release]
AID - 10.1073/pnas.86.8.2938 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1989 Apr;86(8):2938-42. doi: 10.1073/pnas.86.8.2938.