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Mapping Interpuff Interval Distribution to the Properties of Inositol Trisphosphate Receptors.

ABSTRACT: Tightly clustered inositol trisphosphate receptors (IP3Rs) control localized Ca2+ liberation from the endoplasmic reticulum to generate repetitive Ca2+ puffs. Distributions of the interpuff interval (IPI), i.e., the waiting time between successive puffs, are found to be well characterized by a probability density function involving only two parameters, ? and ?, which represent the basal rate of puff generation and the recovery rate from refractoriness, respectively. However, how the two parameters depend on the kinetic parameters of single IP3Rs in a cluster is still unclear. In this article, using a stochastic puff model and a single-channel data-based IP3R model, we establish the dependencies of ? and ? on two important IP3R model parameters, IP3 concentration ([IP3]) and the recovery rate from Ca2+ inhibition (rlow). By varying [IP3] and rlow in physiologically plausible ranges, we find that the ?-? plane is comprised of only two disjoint regions, a biologically impermissible region and a region where each parameter set (?, ?) can be caused by using two different combinations of [IP3] and rlow. The two combinations utilize very different mechanisms to maintain the same IPI distribution, and the mechanistic difference provides a way of identifying IP3R kinetic parameters by observing properties of the IPI.

SUBMITTER: Cao P

PROVIDER: S-EPMC5448242 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Mapping Interpuff Interval Distribution to the Properties of Inositol Trisphosphate Receptors.

Cao Pengxing P Falcke Martin M Sneyd James J

Biophysical journal 20170501 10

Tightly clustered inositol trisphosphate receptors (IP3Rs) control localized Ca2+ liberation from the endoplasmic reticulum to generate repetitive Ca2+ puffs. Distributions of the interpuff interval (IPI), i.e., the waiting time between successive puffs, are found to be well characterized by a probability density function involving only two parameters, λ and ξ, which represent the basal rate of puff generation and the recovery rate from refractoriness, respective ...[more]

PMID: 28538151

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Project description:RationaleThe mechanisms underlying atrial fibrillation (AF), the most common clinical arrhythmia, are poorly understood. Nucleoplasmic Ca2+ regulates gene expression, but the nature and significance of nuclear Ca2+-changes in AF are largely unknown.ObjectiveTo elucidate mechanisms by which AF alters atrial-cardiomyocyte nuclear Ca2+ ([Ca2+]Nuc) and CaMKII (Ca2+/calmodulin-dependent protein kinase-II)-related signaling.Methods and resultsAtrial cardiomyocytes were isolated from control and AF dogs (kept in AF by atrial tachypacing [600 bpm × 1 week]). [Ca2+]Nuc and cytosolic [Ca2+] ([Ca2+]Cyto) were recorded via confocal microscopy. Diastolic [Ca2+]Nuc was greater than [Ca2+]Cyto under control conditions, while resting [Ca2+]Nuc was similar to [Ca2+]Cyto; both diastolic and resting [Ca2+]Nuc increased with AF. IP3R (Inositol-trisphosphate receptor) stimulation produced larger [Ca2+]Nuc increases in AF versus control cardiomyocytes, and IP3R-blockade suppressed the AF-related [Ca2+]Nuc differences. AF upregulated nuclear protein expression of IP3R1 (IP3R-type 1) and of phosphorylated CaMKII (immunohistochemistry and immunoblot) while decreasing the nuclear/cytosolic expression ratio for HDAC4 (histone deacetylase type-4). Isolated atrial cardiomyocytes tachypaced at 3 Hz for 24 hours mimicked AF-type [Ca2+]Nuc changes and L-type calcium current decreases versus 1-Hz-paced cardiomyocytes; these changes were prevented by IP3R knockdown with short-interfering RNA directed against IP3R1. Nuclear/cytosolic HDAC4 expression ratio was decreased by 3-Hz pacing, while nuclear CaMKII phosphorylation was increased. Either CaMKII-inhibition (by autocamtide-2-related peptide) or IP3R-knockdown prevented the CaMKII-hyperphosphorylation and nuclear-to-cytosolic HDAC4 shift caused by 3-Hz pacing. In human atrial cardiomyocytes from AF patients, nuclear IP3R1-expression was significantly increased, with decreased nuclear/nonnuclear HDAC4 ratio. MicroRNA-26a was predicted to target ITPR1 (confirmed by luciferase assay) and was downregulated in AF atrial cardiomyocytes; microRNA-26a silencing reproduced AF-induced IP3R1 upregulation and nuclear diastolic Ca2+-loading.ConclusionsAF increases atrial-cardiomyocyte nucleoplasmic [Ca2+] by IP3R1-upregulation involving miR-26a, leading to enhanced IP3R1-CaMKII-HDAC4 signaling and L-type calcium current downregulation. Graphic Abstract: A graphic abstract is available for this article.

Dataset Information

Mapping Interpuff Interval Distribution to the Properties of Inositol Trisphosphate Receptors.

Publications

Mapping Interpuff Interval Distribution to the Properties of Inositol Trisphosphate Receptors.

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