title: Calcium signaling recruits substrate transporters GLUT4 and CD36 to the sarcolemma without increasing cardiac substrate uptake.
abstract: Activation of AMP-activated protein kinase (AMPK) in cardiomyocytes induces translocation of glucose transporter GLUT4 and long-chain fatty acid (LCFA) transporter CD36 from endosomal stores to the sarcolemma to enhance glucose and LCFA uptake, respectively. Ca(2+)/calmodulin-activated kinase kinase-β (CaMKKβ) has been positioned directly upstream of AMPK. However, it is unknown whether acute increases in [Ca(2+)]i stimulate translocation of GLUT4 and CD36 and uptake of glucose and LCFA or whether Ca(2+) signaling converges with AMPK signaling to exert these actions. Therefore, we studied the interplay between Ca(2+) and AMPK signaling in regulation of cardiomyocyte substrate uptake. Exposure of primary cardiomyocytes to inhibitors or activators of Ca(2+) signaling affected neither AMPK-Thr(172) phosphorylation nor basal and AMPK-mediated glucose and LCFA uptake. Despite their lack of an effect on substrate uptake, Ca(2+) signaling activators induced GLUT4 and CD36 translocation. In contrast, AMPK activators stimulated GLUT4/CD36 translocation as well as glucose/LCFA uptake. When cardiomyocytes were cotreated with Ca(2+) signaling and AMPK activators, Ca(2+) signaling activators further enhanced AMPK-induced glucose/LCFA uptake. In conclusion, Ca(2+) signaling shows no involvement in AMPK-induced GLUT4/CD36 translocation and substrate uptake but elicits transporter translocation via a separate pathway requiring CaMKKβ/CaMKs. Ca(2+)-induced transporter translocation by itself appears to be ineffective to increase substrate uptake but requires additional AMPK activation to effectuate transporter translocation into increased substrate uptake. Ca(2+)-induced transporter translocation might be crucial under excessive cardiac stress conditions that require supraphysiological energy demands. Alternatively, Ca(2+) signaling might prepare the heart for substrate uptake during physiological contraction by inducing transporter translocation.
authors.affiliation: Departments of Molecular Genetics.
authors.forename: Yeliz
authors.initials: Y
authors.lastname: Angin
authors.affiliation: Departments of Molecular Genetics.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schwenk
authors.affiliation: Biochemistry and.
authors.forename: Reyhan
authors.initials: R
authors.lastname: Nergiz-Unal
authors.affiliation: Departments of Molecular Genetics.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hoebers
authors.affiliation: Biochemistry and.
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk
authors.affiliation: Biochemistry and.
authors.forename: Marijke J
authors.initials: MJ
authors.lastname: Kuijpers
authors.affiliation: Departments of Molecular Genetics.
authors.forename: Will A
authors.initials: WA
authors.lastname: Coumans
authors.affiliation: Molecular Cell Biology, School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands;
authors.forename: Marc A M J
authors.initials: MA
authors.lastname: van Zandvoort
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Arend
authors.initials: A
authors.lastname: Bonen
authors.affiliation: Departments of Molecular Genetics.
authors.forename: Dietbert
authors.initials: D
authors.lastname: Neumann
authors.affiliation: Departments of Molecular Genetics.
authors.forename: Jan F C
authors.initials: JF
authors.lastname: Glatz
authors.affiliation: Departments of Molecular Genetics, j.luiken@maastrichtuniversity.nl.
authors.forename: Joost J F P
authors.initials: JJ
authors.lastname: Luiken
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D018955:CD36 Antigens; C008132:Cd36 protein, rat; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; C495694:Slc2a4 protein, rat; D000001:Calcimycin; D019284:Thapsigargin; D005947:Glucose
keywords: AMP-activated protein kinase; CD36; Ca2+/calmodulin-activated kinases; cardiomyocytes; glucose transporter 4