title: Abnormal distribution of inositol 1,4,5-trisphosphate receptors in human muscle can be related to altered calcium signals and gene expression in Duchenne dystrophy-derived cells.
abstract: Inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)Rs) drive calcium signals involved in skeletal muscle excitation-transcription coupling and plasticity; IP(3)R subtype distribution and downstream events evoked by their activation have not been studied in human muscle nor has their possible alteration in Duchenne muscular dystrophy (DMD). We studied the expression and localization of IP(3)R subtypes in normal and DMD human muscle and in normal (RCMH) and dystrophic (RCDMD) human muscle cell lines. In normal muscle, both type 1 IP(3)Rs (IP(3)R1) and type 2 IP(3)Rs (IP(3)R2) show a higher expression in type II fibers, whereas type 3 IP(3)Rs (IP(3)R3) show uniform distribution. In DMD biopsies, all fibers display a homogeneous IP(3)R2 label, whereas 24 +/- 7% of type II fibers have lost the IP(3)R1 label. RCDMD cells show 5-fold overexpression of IP(3)R2 and down-regulation of IP(3)R3 compared with RCMH cells. A tetanic stimulus induces IP(3)-dependent slow Ca(2+) transients significantly larger and faster in RCDMD cells than in RCMH cells as well as significant ERK1/2 phosphorylation in normal but not in dystrophic cells. Excitation-driven gene expression was different among cell lines; 44 common genes were repressed in RCMH cells and expressed in RCDMD cells or vice versa. IP(3)-dependent Ca(2+) release may play a significant role in DMD pathophysiology.
authors.affiliation: Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago 7, Chile.
authors.forename: César
authors.initials: C
authors.lastname: Cárdenas
authors.forename: Nevenka
authors.initials: N
authors.lastname: Juretić
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Bevilacqua
authors.forename: Isaac E
authors.initials: IE
authors.lastname: García
authors.forename: Reinaldo
authors.initials: R
authors.lastname: Figueroa
authors.forename: Ricardo
authors.initials: R
authors.lastname: Hartley
authors.forename: Ana L
authors.initials: AL
authors.lastname: Taratuto
authors.forename: Roger
authors.initials: R
authors.lastname: Gejman
authors.forename: Nora
authors.initials: N
authors.lastname: Riveros
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.forename: Enrique
authors.initials: E
authors.lastname: Jaimovich
mesh_terms: D015153:Blotting, Western; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D004558:Electric Stimulation; D005786:Gene Expression Regulation; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3