title: β-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3.
abstract: Free fatty acids receptor 3 (FFA3, GPR41) and 2 (FFA2, GPR43), for which the short-chain fatty acids (SCFAs) acetate and propionate are agonist, have emerged as important G-protein-coupled receptors influenced by diet and gut flora composition. A recent study (Kimura et al., 2011) demonstrated functional expression of FFA3 in the rodent sympathetic nervous system (SNS) providing a potential link between nutritional status and autonomic function. However, little is known of the source of endogenous ligands, signaling pathways, or effectors in sympathetic neurons. In this study, we found that FFA3 and FFA2 are unevenly expressed in the rat SNS with higher transcript levels in prevertebral (e.g., celiac-superior mesenteric and major pelvic) versus paravertebral (e.g., superior cervical and stellate) ganglia. FFA3, whether heterologously or natively expressed, coupled via PTX-sensitive G-proteins to produce voltage-dependent inhibition of N-type Ca(2+) channels (Cav2.2) in sympathetic neurons. In addition to acetate and propionate, we show that β-hydroxybutyrate (BHB), a metabolite produced during ketogenic conditions, is also an FFA3 agonist. This contrasts with previous interpretations of BHB as an antagonist at FFA3. Together, these results indicate that endogenous BHB levels, especially when elevated under certain conditions, such as starvation, diabetic ketoacidosis, and ketogenic diets, play a potentially important role in regulating the activity of the SNS through FFA3.
authors.affiliation: Section on Transmitter Signaling, Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-9411.
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Won
authors.forename: Van B
authors.initials: VB
authors.lastname: Lu
authors.forename: Henry L
authors.initials: HL
authors.lastname: Puhl
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Ikeda
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology*; D000818:Animals; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D055724:Electrophysiological Phenomena / Q000502:physiology; D031541:Fluorescence Resonance Energy Transfer; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D017403:In Situ Hybridization; D007657:Ketone Bodies / Q000494:pharmacology; D008024:Ligands; D008297:Male; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000502:physiology*; D014162:Transfection
chemical_list: D020864:Calcium Channels, N-Type; D018076:DNA, Complementary; C506482:Gpcr41 protein, mouse; D007657:Ketone Bodies; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D020155:3-Hydroxybutyric Acid