Abstract
Lipoic acid (LA) is a naturally occurring fatty acid that exhibits anti-oxidant and anti-inflammatory properties and is being pursued as a therapeutic for many diseases including multiple sclerosis, diabetic polyneuropathy and Alzheimer's disease. We previously reported on the novel finding that racemic LA (50:50 mixture of R-LA and S-LA) stimulates cAMP production, activates prostanoid EP2 and EP4 receptors and adenylyl cyclases (AC), and suppresses activation and cytotoxicity in NK cells. In this study, we present evidence that furthers our understanding of the mechanisms of action of LA. Using various LA derivatives, such as dihydrolipoic acid (DHLA), S,. S-dimethyl lipoic acid (DMLA) and lipoamide (LPM), we discovered that only LA is capable of stimulating cAMP production in NK cells. Furthermore, there is no difference in cAMP production after stimulation with either R-LA, S-LA or racemic LA. Competition and synergistic studies indicate that LA may also activate AC independent of the EP2 and EP4 receptors. Pretreatment of PBMCs with KH7 (a specific peptide inhibitor of soluble AC) and the calcium inhibitor (Bapta) prior to LA treatment resulted in reduced cAMP levels, suggesting that soluble AC and calcium signaling mediate LA stimulation of cAMP production. In addition, pharmacological inhibitor studies demonstrate that LA also activates other G protein-coupled receptors, including histamine and adenosine but not the β-adrenergic receptors. These novel findings provide information to better understand the mechanisms of action of LA, which can help facilitate the use of LA as a therapeutic for various diseases.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 681-690 |
| Number of pages | 10 |
| Journal | Journal of Nutritional Biochemistry |
| Volume | 22 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2011 |
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Keywords
- Adenylyl cyclase
- CAMP
- G protein-coupled receptors
- Lipoic acid
ASJC Scopus subject areas
- Biochemistry
- Clinical Biochemistry
- Molecular Biology
- Endocrinology, Diabetes and Metabolism
- Nutrition and Dietetics
Cite this
Lipoic acid stimulates cAMP production via G protein-coupled receptor-dependent and -independent mechanisms. / Salinthone, Sonemany; Schillace, Robynn V.; Tsang, Catherine; Regan, John W.; Bourdette, Dennis; Carr, Daniel.
In: Journal of Nutritional Biochemistry, Vol. 22, No. 7, 07.2011, p. 681-690.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Lipoic acid stimulates cAMP production via G protein-coupled receptor-dependent and -independent mechanisms
AU - Salinthone, Sonemany
AU - Schillace, Robynn V.
AU - Tsang, Catherine
AU - Regan, John W.
AU - Bourdette, Dennis
AU - Carr, Daniel
PY - 2011/7
Y1 - 2011/7
N2 - Lipoic acid (LA) is a naturally occurring fatty acid that exhibits anti-oxidant and anti-inflammatory properties and is being pursued as a therapeutic for many diseases including multiple sclerosis, diabetic polyneuropathy and Alzheimer's disease. We previously reported on the novel finding that racemic LA (50:50 mixture of R-LA and S-LA) stimulates cAMP production, activates prostanoid EP2 and EP4 receptors and adenylyl cyclases (AC), and suppresses activation and cytotoxicity in NK cells. In this study, we present evidence that furthers our understanding of the mechanisms of action of LA. Using various LA derivatives, such as dihydrolipoic acid (DHLA), S,. S-dimethyl lipoic acid (DMLA) and lipoamide (LPM), we discovered that only LA is capable of stimulating cAMP production in NK cells. Furthermore, there is no difference in cAMP production after stimulation with either R-LA, S-LA or racemic LA. Competition and synergistic studies indicate that LA may also activate AC independent of the EP2 and EP4 receptors. Pretreatment of PBMCs with KH7 (a specific peptide inhibitor of soluble AC) and the calcium inhibitor (Bapta) prior to LA treatment resulted in reduced cAMP levels, suggesting that soluble AC and calcium signaling mediate LA stimulation of cAMP production. In addition, pharmacological inhibitor studies demonstrate that LA also activates other G protein-coupled receptors, including histamine and adenosine but not the β-adrenergic receptors. These novel findings provide information to better understand the mechanisms of action of LA, which can help facilitate the use of LA as a therapeutic for various diseases.
AB - Lipoic acid (LA) is a naturally occurring fatty acid that exhibits anti-oxidant and anti-inflammatory properties and is being pursued as a therapeutic for many diseases including multiple sclerosis, diabetic polyneuropathy and Alzheimer's disease. We previously reported on the novel finding that racemic LA (50:50 mixture of R-LA and S-LA) stimulates cAMP production, activates prostanoid EP2 and EP4 receptors and adenylyl cyclases (AC), and suppresses activation and cytotoxicity in NK cells. In this study, we present evidence that furthers our understanding of the mechanisms of action of LA. Using various LA derivatives, such as dihydrolipoic acid (DHLA), S,. S-dimethyl lipoic acid (DMLA) and lipoamide (LPM), we discovered that only LA is capable of stimulating cAMP production in NK cells. Furthermore, there is no difference in cAMP production after stimulation with either R-LA, S-LA or racemic LA. Competition and synergistic studies indicate that LA may also activate AC independent of the EP2 and EP4 receptors. Pretreatment of PBMCs with KH7 (a specific peptide inhibitor of soluble AC) and the calcium inhibitor (Bapta) prior to LA treatment resulted in reduced cAMP levels, suggesting that soluble AC and calcium signaling mediate LA stimulation of cAMP production. In addition, pharmacological inhibitor studies demonstrate that LA also activates other G protein-coupled receptors, including histamine and adenosine but not the β-adrenergic receptors. These novel findings provide information to better understand the mechanisms of action of LA, which can help facilitate the use of LA as a therapeutic for various diseases.
KW - Adenylyl cyclase
KW - CAMP
KW - G protein-coupled receptors
KW - Lipoic acid
UR - http://www.scopus.com/inward/record.url?scp=79953896769&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953896769&partnerID=8YFLogxK
U2 - 10.1016/j.jnutbio.2010.05.008
DO - 10.1016/j.jnutbio.2010.05.008
M3 - Article
C2 - 21036588
AN - SCOPUS:79953896769
VL - 22
SP - 681
EP - 690
JO - Journal of Nutritional Biochemistry
JF - Journal of Nutritional Biochemistry
SN - 0955-2863
IS - 7
ER -