title: Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules.
abstract: Mice with three amino acid mutations in the calmodulin binding domain of type-2 ryanodine receptor ion channel (Ryr2(ADA/ADA) mice) have impaired intracellular Ca(2+) handling and cardiac hypertrophy with death at an early age. In this report, the role of signaling molecules implicated in cardiac hypertrophy of Ryr2(ADA/ADA) mice was investigated. Calcineurin A-β (CNA-β) and nuclear factor of activated T cell (NFAT) signaling were monitored in mice carrying either luciferase transgene driven by NFAT-dependent promoter or knockout of CNA-β. NFAT transcriptional activity in Ryr2(ADA/ADA) hearts was not markedly upregulated at embryonic day 16.5 compared with wild-type but significantly increased at postnatal days 1 and 10. Ablation of CNA-β extended the life span of Ryr2(ADA/ADA) mice and enhanced cardiac function without improving sarcoplasmic reticulum Ca(2+) handling or suppressing the expression of genes implicated in cardiac hypertrophy. Embryonic day 16.5 Ryr2(ADA/ADA) mice had normal heart weights with no major changes in Akt1 and class II histone deacetylase phosphorylation and myocyte enhancer factor-2 activity. In contrast, phosphorylation levels of Erk1/2, p90 ribosomal S6 kinases (p90RSKs), and GSK-3β were increased in hearts of embryonic day 16.5 homozygous mutant mice. The results indicate that an impaired calmodulin regulation of RyR2 was neither associated with an altered CNA-β/NFAT, class II histone deacetylase (HDAC)/MEF2, nor Akt signaling in embryonic day 16.5 hearts; rather increased Erk1/2 and p90RSK phosphorylation levels likely leading to reduced GSK-3β activity were found to precede development of cardiac hypertrophy in mice expressing dysfunctional ryanodine receptor ion channel.
authors.affiliation: Dept. of Biochemistry and Biophysics, Univ. of North Carolina, Chapel Hill, NC 27599-7260, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Asima
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pasek
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Gerhard
authors.initials: G
authors.lastname: Meissner
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D006332:Cardiomegaly / Q000503:physiopathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000196:embryology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D050778:NFATC Transcription Factors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D050778:NFATC Transcription Factors; D019837:Ryanodine Receptor Calcium Release Channel; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; C557393:protein phosphatase 3, catalytic subunit, beta isoform, mouse