Danny McCoyne
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Hi,

Does anybody know the effect these would have on in vitro mouse Fibroblasts? I.e. proliferation growth? I know both would upregulate adenylyl cyclase and hence increase cAMP levels.
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thegodofgod
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(Original post by Danny McCoyne)
Hi,

Does anybody know the effect these would have on in vitro mouse Fibroblasts? I.e. proliferation growth? I know both would upregulate adenylyl cyclase and hence increase cAMP levels.
I know that beta-blockers are being trialled for use in cancer, so it would make sense that adrenaline (being a beta-adrenergic receptor agonist) would increase proliferation of these fibroblasts. However, bear in mind that adrenaline also activates alpha-adrenergic receptors with roughly equal affinity as beta-adrenergic receptors, and so activation of alpha1-adrenergic receptor activation would lead to increased intracellular IP3, as the alpha1-adrenergic receptor is a Gq-coupled GPCR.
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Danny McCoyne
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Does forskolin do the same thing?
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zombiejon
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Which type of fibroblast?

Dubey RK. Endogenous cyclic AMP-adenosine pathway regulates cardiac fibroblast growth < - Rat primary cell ex vivo model. 24hr treatment with forskolin/norepinephrine increased cAMP production, and decreased DNA synthesis.

Schmitt JM. Cyclic AMP-Mediated Inhibition of Cell Growth Requires the Small G Protein Rap1. < - NIH 3T3 murine embryo fibroblast cell line (in vitro). cAMP production induced by forskolin resulted in the inhibition of the MAPK signaling cascade in a Rap1 dependent manner, thereby reducing cell proliferation.

Weinberg E. Prostaglandin E2 inhibits the proliferation of human gingival fibroblasts via the EP2 receptor and Epac. < - In vitro human cell line. PGE2/forskolin both have inhibitory effects upon gingival fibroblast proliferation (PGE2 acted via EP2 > cAMP > Epac).
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Danny McCoyne
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(Original post by zombiejon)
Which type of fibroblast?

Dubey RK. Endogenous cyclic AMP-adenosine pathway regulates cardiac fibroblast growth < - Rat primary cell ex vivo model. 24hr treatment with forskolin/norepinephrine increased cAMP production, and decreased DNA synthesis.

Schmitt JM. Cyclic AMP-Mediated Inhibition of Cell Growth Requires the Small G Protein Rap1. < - NIH 3T3 murine embryo fibroblast cell line (in vitro). cAMP production induced by forskolin resulted in the inhibition of the MAPK signaling cascade in a Rap1 dependent manner, thereby reducing cell proliferation.

Weinberg E. Prostaglandin E2 inhibits the proliferation of human gingival fibroblasts via the EP2 receptor and Epac. < - In vitro human cell line. PGE2/forskolin both have inhibitory effects upon gingival fibroblast proliferation (PGE2 acted via EP2 > cAMP > Epac).
Ltk fibroblasts
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Danny McCoyne
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thegodofgod
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(Original post by Danny McCoyne)
Does forskolin do the same thing?
Forskolin acts further downstream to adrenaline. Adrenaline activates cell-surface alpha- and beta-adrenergic receptors, which are G-protein-coupled receptors (GPCRs). Beta-adrenergic receptors all activate the Gs protein, causing activation of the enzyme adenylyl cyclase, which hydrolyses ATP to cAMP. Forskolin, on the other hand, activates the enzyme adenylyl cyclase directly (avoiding GPCR activation), increasing ATP hydrolysis to cAMP. So overall, adrenaline and forskolin both have the same net effect of increasing the intracellular cAMP concentration, although they have different targets within the same signal transduction pathway.
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Danny McCoyne
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(Original post by thegodofgod)
Forskolin acts further downstream to adrenaline. Adrenaline activates cell-surface alpha- and beta-adrenergic receptors, which are G-protein-coupled receptors (GPCRs). Beta-adrenergic receptors all activate the Gs protein, causing activation of the enzyme adenylyl cyclase, which hydrolyses ATP to cAMP. Forskolin, on the other hand, activates the enzyme adenylyl cyclase directly (avoiding GPCR activation), increasing ATP hydrolysis to cAMP. So overall, adrenaline and forskolin both have the same net effect of increasing the intracellular cAMP concentration, although they have different targets within the same signal transduction pathway.

Thanks you're very clear in your explanation.

Just one final thing would Forskolin result in more proliferation compared to Adrenaline since Forskolin cut to the chase?
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thegodofgod
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(Original post by Danny McCoyne)
Thanks you're very clear in your explanation.

Just one final thing would Forskolin result in more proliferation compared to Adrenaline since Forskolin cut to the chase?
No worries

Potentially. If you have equimolar adrenaline and forskolin and they're both equipotent in terms of their EC50 on their respective targets, you may be able to argue that some adrenaline molecules would not activate some beta-adrenergic receptors, or that some beta-adrenergic receptors may not activate some Gs proteins, and that some Gs proteins may not activate adenylyl cyclase.
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jessicaaaahxx
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I'm looking at this for a piece of coursework and I'm struggling to find anything vaguely scientific relating to forskolin's mode of action, only health websites that say it increases cAMP and help you lose weight (?!). Do you have any articles or anything on forskolin's mode of action. Afraid I can't reference this forum in my lab report lol
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zombiejon
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Best bet is this review:

Hurley JH. Structure, Mechanism, and Regulation of Mammalian Adenylyl Cyclase. J Biol Chem 1999; 274.

Or were you specifically referring to adipocyte activation?
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jessicaaaahxx
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(Original post by zombiejon)
Best bet is this review:

Hurley JH. Structure, Mechanism, and Regulation of Mammalian Adenylyl Cyclase. J Biol Chem 1999; 274.

Or were you specifically referring to adipocyte activation?
No that's fine thank you
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