Lipoic acid stimulates cAMP production via G protein-coupled receptor-dependent and -independent mechanisms

Sonemany Salinthone, Robynn V. Schillace, Catherine Tsang, John W. Regan, Dennis Bourdette, Daniel Carr

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)681-690
Number of pages10
JournalJournal of Nutritional Biochemistry
Volume22
Issue number7
DOIs
StatePublished - Jul 2011

Fingerprint

Thioctic Acid
G-Protein-Coupled Receptors
Adenylyl Cyclases
Natural Killer Cells
Receptors, Prostaglandin E, EP2 Subtype
Receptors, Prostaglandin E, EP4 Subtype
Calcium
Calcium Signaling
Diabetic Neuropathies

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 journalArticle

Salinthone, Sonemany ; Schillace, Robynn V. ; Tsang, Catherine ; Regan, John W. ; Bourdette, Dennis ; Carr, Daniel. / Lipoic acid stimulates cAMP production via G protein-coupled receptor-dependent and -independent mechanisms. In: Journal of Nutritional Biochemistry. 2011 ; Vol. 22, No. 7. pp. 681-690.
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