title: Intracellular long-chain acyl CoAs activate TRPV1 channels.
abstract: TRPV1 channels are an important class of membrane proteins that play an integral role in the regulation of intracellular cations such as calcium in many different tissue types. The anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) is a known positive modulator of TRPV1 channels and the negatively charged phosphate groups interact with several basic amino acid residues in the proximal C-terminal TRP domain of the TRPV1 channel. We and other groups have shown that physiological sub-micromolar levels of long-chain acyl CoAs (LC-CoAs), another ubiquitous anionic lipid, can also act as positive modulators of ion channels and exchangers. Therefore, we investigated whether TRPV1 channel activity is similarly regulated by LC-CoAs. Our results show that LC-CoAs are potent activators of the TRPV1 channel and interact with the same PIP2-binding residues in TRPV1. In contrast to PIP2, LC-CoA modulation of TRPV1 is independent of Ca2+i, acting in an acyl side-chain saturation and chain-length dependent manner. Elevation of LC-CoAs in intact Jurkat T-cells leads to significant increases in agonist-induced Ca2+i levels. Our novel findings indicate that LC-CoAs represent a new fundamental mechanism for regulation of TRPV1 channel activity that may play a role in diverse cell types under physiological and pathophysiological conditions that alter fatty acid transport and metabolism such as obesity and diabetes.
authors.affiliation: Department of Pharmacology, Alberta Diabetes Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Alberta Diabetes Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Chris R J
authors.initials: CR
authors.lastname: Carter
authors.affiliation: Department of Pharmacology, Alberta Diabetes Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Nermeen
authors.initials: N
authors.lastname: Youssef
authors.affiliation: Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.affiliation: Department of Pharmacology, Alberta Diabetes Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Light
mesh_terms: D000214:Acyl Coenzyme A / Q000737:chemistry*; D000595:Amino Acid Sequence; D002118:Calcium / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008055:Lipids / Q000737:chemistry; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010171:Palmitoyl Coenzyme A / Q000737:chemistry; D018408:Patch-Clamp Techniques; D010716:Phosphatidylinositols / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D050916:TRPV Cation Channels / Q000502:physiology*
chemical_list: D000214:Acyl Coenzyme A; D005227:Fatty Acids; D008055:Lipids; D010716:Phosphatidylinositols; D010743:Phospholipids; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D010171:Palmitoyl Coenzyme A; D002118:Calcium