• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Jun 1981; 78(6): 3363–3367.
PMCID: PMC319568

Forskolin: unique diterpene activator of adenylate cyclase in membranes and in intact cells.

Abstract

The diterpene, forskolin [half-maximal effective concentration (EC50), 5-10 microM] activates adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] in rat cerebral cortical membranes in a rapid and reversible manner. Activation is not dependent on exogenous guanyl nucleotides and is not inhibited by guanosine 5'-O-(2-thiodiphosphate) when assayed with adenosine 5'-[beta, gamma-imido]triphosphate as substrate. GTP and GDP potentiate responses to forskolin. The activations of adenylate cyclase by forskolin and guanosine 5'-[beta, gamma-imido]triphosphate p[NH]ppG are not additive, whereas activations by forskolin and fluoride are additive or partially additive. The responses of adenylate cyclase to forskolin or fluoride are not inhibited by manganese ions, whereas the response to p[NH]ppG is completely blocked. Activation of adenylate cyclase by forskolin is considerably greater than the activation by fluoride in membranes from rat cerebellum, striatum, heart, and liver, while being about equal or less than the activation by fluoride in other tissues. Forskolin (EC50, 25 microM) causes a rapid and readily reversible 35-fold elevation of cyclic AMP in rat cerebral cortical slices that is not blocked by a variety of neurotransmitter antagonists. Low concentrations of forskolin (1 microM) augment the response of cyclic AMP-generating systems in brain slices to norepinephrine, isoproterenol, histamine, adenosine, prostaglandin E2, and vasoactive intestinal peptide. Forskolin would appear to activate adenylate cyclase through a unique mechanism involving both direct activation of the enzyme and facilitation or potentiation of the modulation of enzyme activity by receptors or the guanyl nucleotide-binding subunit, or both.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.0M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Rodbell M. The role of hormone receptors and GTP-regulatory proteins in membrane transduction. Nature. 1980 Mar 6;284(5751):17–22. [PubMed]
  • Perkins JP. Adenyl cyclase. Adv Cyclic Nucleotide Res. 1973;3:1–64. [PubMed]
  • Londos C, Salomon Y, Lin MC, Harwood JP, Schramm M, Wolff J, Rodbell M. 5'-Guanylylimidodiphosphate, a potent activator of adenylate cyclase systems in eukaryotic cells. Proc Natl Acad Sci U S A. 1974 Aug;71(8):3087–3090. [PMC free article] [PubMed]
  • Londos C, Lad PM, Nielsen TB, Rodbell M. Solubilization and conversion of hepatic adenylate cyclase to a form requiring MnATP as substrate. J Supramol Struct. 1979;10(1):31–37. [PubMed]
  • Neer EJ. Physical and functional properties of adenylate cyclase from mature rat testis. J Biol Chem. 1978 Aug 25;253(16):5808–5812. [PubMed]
  • Bradham LS, Holt DA, Sims M. The effect of Ca2+ on the adenyl cyclase of calf brain. Biochim Biophys Acta. 1970 Feb 24;201(2):250–260. [PubMed]
  • Moss J, Vaughan M. Activation of adenylate cyclase by choleragen. Annu Rev Biochem. 1979;48:581–600. [PubMed]
  • Lindner E, Dohadwalla AN, Bhattacharya BK. Positive inotropic and blood pressure lowering activity of a diterpene derivative isolated from Coleus forskohli: Forskolin. Arzneimittelforschung. 1978;28(2):284–289. [PubMed]
  • Salomon Y, Londos C, Rodbell M. A highly sensitive adenylate cyclase assay. Anal Biochem. 1974 Apr;58(2):541–548. [PubMed]
  • Perkins JP, Moore MM. Adenyl cyclase of rat cerebral cortex. Activation of sodium fluoride and detergents. J Biol Chem. 1971 Jan 10;246(1):62–68. [PubMed]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed]
  • Schramm M, Rodbell M. A persistent active state of the adenylate cyclase system produced by the combined actions of isoproterenol and guanylyl imidodiphosphate in frog erythrocyte membranes. J Biol Chem. 1975 Mar 25;250(6):2232–2237. [PubMed]
  • Clark RB. Endogenous GTP and the regulation of epinephrine stimulation of adenylate cyclase. J Cyclic Nucleotide Res. 1978 Apr;4(2):71–85. [PubMed]
  • Howlett AC, Sternweis PC, Macik BA, Van Arsdale PM, Gilman AG. Reconstitution of catecholamine-sensitive adenylate cyclase. Association of a regulatory component of the enzyme with membranes containing the catalytic protein and beta-adrenergic receptors. J Biol Chem. 1979 Apr 10;254(7):2287–2295. [PubMed]
  • Limbird LE, Hickey AR, Lefkowitz RJ. Unique uncoupling of the frog erythrocyte adenylate cyclase system by manganese. Loss of hormone and guanine nucleotide-sensitive enzyme activities without loss of nucleotide-sensitive, high affinity agonist binding. J Biol Chem. 1979 Apr 25;254(8):2677–2683. [PubMed]
  • Downs RW, Jr, Spiegel AM, Singer M, Reen S, Aurbach GD. Fluoride stimulation of adenylate cyclase is dependent on the guanine nucleotide regulatory protein. J Biol Chem. 1980 Feb 10;255(3):949–954. [PubMed]
  • Eckstein F, Cassel D, Levkovitz H, Lowe M, Selinger Z. Guanosine 5'-O-(2-thiodiphosphate). An inhibitor of adenylate cyclase stimulation by guanine nucleotides and fluoride ions. J Biol Chem. 1979 Oct 10;254(19):9829–9834. [PubMed]
  • Schultz J, Daly JW. Cyclic adenosine 3',5'-monophosphate in guinea pig cerebral cortical slices. I. Formation of cyclic adenosine 3',5'-monophosphate from endogenous adenosine triphosphate and from radioactive adenosine triphosphate formed during a prior incubation with radioactive adenine. J Biol Chem. 1973 Feb 10;248(3):843–852. [PubMed]
  • Schwabe U, Miyake M, Ohga Y, Daly JW. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711): a potent inhibitor of adenosine cyclic 3',5'-monophosphate phosphodiesterases in homogenates and tissue slices from rat brain. Mol Pharmacol. 1976 Nov;12(6):900–910. [PubMed]
  • Cassel D, Selinger Z. Mechanism of adenylate cyclase activation by cholera toxin: inhibition of GTP hydrolysis at the regulatory site. Proc Natl Acad Sci U S A. 1977 Aug;74(8):3307–3311. [PMC free article] [PubMed]
  • Gill DM, Meren R. ADP-ribosylation of membrane proteins catalyzed by cholera toxin: basis of the activation of adenylate cyclase. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3050–3054. [PMC free article] [PubMed]
  • Cassel D, Pfeuffer T. Mechanism of cholera toxin action: covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system. Proc Natl Acad Sci U S A. 1978 Jun;75(6):2669–2673. [PMC free article] [PubMed]
  • Johnson GL, Kaslow HR, Bourne HR. Reconstitution of cholera toxin-activated adenylate cyclase. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3113–3117. [PMC free article] [PubMed]
  • Partington CR, Daly JW. Effect of gangliosides on adenylate cyclase activity in rat cerebral cortical membranes. Mol Pharmacol. 1979 May;15(3):484–491. [PubMed]
  • Cheung WY, Bradham LS, Lynch TJ, Lin YM, Tallant EA. Protein activator of cyclic 3':5'-nucleotide phosphodiesterase of bovine or rat brain also activates its adenylate cyclase. Biochem Biophys Res Commun. 1975 Oct 6;66(3):1055–1062. [PubMed]
  • Brostrom CO, Huang YC, Breckenridge BM, Wolff DJ. Identification of a calcium-binding protein as a calcium-dependent regulator of brain adenylate cyclase. Proc Natl Acad Sci U S A. 1975 Jan;72(1):64–68. [PMC free article] [PubMed]
  • Smellie FW, Davis CW, Daly JW, Wells JN. Alkylxanthines: inhibition of adenosine-elicited accumulation of cyclic AMP in brain slices and of brain phosphodiesterase activity. Life Sci. 1979 Jun 25;24(26):2475–2482. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...