title: Cardiac hypertrophy associated with impaired regulation of cardiac ryanodine receptor by calmodulin and S100A1.
abstract: The cardiac ryanodine receptor (RyR2) is inhibited by calmodulin (CaM) and S100A1. Simultaneous substitution of three amino acid residues (W3587A, L3591D, F3603A; RyR2ADA) in the CaM binding domain of RyR2 results in loss of CaM inhibition at submicromolar (diastolic) and micromolar (systolic) Ca²⁺, cardiac hypertrophy, and heart failure in Ryr2ADA/ADA mice. To address whether cardiac hypertrophy results from the elimination of CaM and S100A1 inhibition at diastolic or systolic Ca²⁺, a mutant mouse was generated with a single RyR2 amino acid substitution (L3591D; RyR2D). Here we report that in single-channel measurements RyR2-L3591D isolated from Ryr2D/D hearts lost CaM inhibition at diastolic Ca²⁺ only, whereas S100A1 regulation was eliminated at both diastolic and systolic Ca²⁺. In contrast to the ~2-wk life span of Ryr2ADA/ADA mice, Ryr2D/D mice lived longer than 1 yr. Six-month-old Ryr2D/D mice showed a 9% increase in heart weight-to-body weight ratio, modest changes in cardiac morphology, and a twofold increase in atrial natriuretic peptide mRNA levels compared with wild type. After 4-wk pressure overload with transverse aortic constriction, heart weight-to-body weight ratio and atrial natriuretic peptide mRNA levels increased and echocardiography showed changes in heart morphology of Ryr2D/D mice compared with sham-operated mice. Collectively, the findings indicate that the single RyR2-L3591D mutation, which distinguishes the effects of diastolic and systolic Ca²⁺, alters heart size and cardiac function to a lesser extent in Ryr2D/D mice than the triple mutation in Ryr2ADA/ADA mice. They further suggest that CaM inhibition of RyR2 at systolic Ca²⁺ is important for maintaining normal cardiac function.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Asima
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Tai-Qin
authors.initials: TQ
authors.lastname: Huang
authors.forename: Le
authors.initials: L
authors.lastname: Xu
authors.forename: Angela C
authors.initials: AC
authors.lastname: Gomez
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pasek
authors.forename: Gerhard
authors.initials: G
authors.lastname: Meissner
mesh_terms: D000200:Action Potentials; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D006333:Heart Failure / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D009200:Myocardial Contraction; D012333:RNA, Messenger / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009418:S100 Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002147:Calmodulin; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D009418:S100 Proteins; C110294:S100A1 protein; D009320:Atrial Natriuretic Factor; D002118:Calcium
keywords: S100A1; calmodulin; cardiac hypertrophy; cardiac ryanodine receptor