Differential regulation of two types of intracellular calcium release channels during end-stage heart failure.
The molecular basis of human heart failure is unknown. Alterations in calcium homeostasis have been observed in failing human heart muscles. Intracellular calcium-release channels regulate the calcium flux required for muscle contraction. Two forms of intracellular calcium-release channels are expressed in the heart: the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP3R). In the present study we showed that these two cardiac intracellular calcium release channels were regulated in opposite directions in failing human hearts. In the left ventricle, RyR mRNA levels were decreased by 31% (P < 0.025) whereas IP3R mRNA levels were increased by 123% (P < 0.005). In situ hybridization localized both RyR and IP3R mRNAs to human cardiac myocytes. The relative amounts of IP3 binding sites increased approximately 40% compared with ryanodine binding sites in the failing heart. RyR down-regulation could contribute to impaired contractility; IP3R up regulation may be a compensatory response providing an alternative pathway for mobilizing intracellular calcium release, possibly contributing to the increased diastolic tone associated with heart failure and the hypertrophic response of failing myocardium.
Go
L O
LO
Molecular Medicine Program, Mount Sinai School of Medicine, New York 10029.
Moschella
M C
MC
Watras
J
J
Handa
K K
KK
Fyfe
B S
BS
Marks
A R
AR
D000293:Adolescent; D000328:Adult; D015152:Blotting, Northern; D015220:Calcium Channels / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism; D009202:Cardiomyopathies / Q000378:metabolism*; D002478:Cells, Cultured; D015342:DNA Probes; D005260:Female; D015870:Gene Expression; D006333:Heart Failure / Q000378:metabolism*; D016027:Heart Transplantation; D006706:Homeostasis; D006801:Humans; D017403:In Situ Hybridization; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel
D015220:Calcium Channels; D015342:DNA Probes; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009124:Muscle Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D015544:Inositol 1,4,5-Trisphosphate