| First Author | Shen X | Year | 2022 |
| Journal | Elife | Volume | 11 |
| PubMed ID | 35913125 | Mgi Jnum | J:344111 |
| Mgi Id | MGI:7332458 | Doi | 10.7554/eLife.77725 |
| Citation | Shen X, et al. (2022) Prolonged beta-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure. Elife 11:e77725 |
| abstractText | Ryanodine receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that 'dispersion' of RyR clusters disrupts Ca(2+) homeostasis during heart failure (HF) (Kolstad et al., eLife, 2018). Here, we investigated whether prolonged beta-adrenergic stimulation, a hallmark of HF, promotes RyR cluster dispersion and examined the underlying mechanisms. We observed that treatment of healthy rat cardiomyocytes with isoproterenol for 1 hr triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) reversed these effects, while cluster dispersion was reproduced by specific activation of CaMKII, and in mice with constitutively active Ser2814-RyR. A similar role of protein kinase A (PKA) in promoting RyR cluster fragmentation was established by employing PKA activation or inhibition. Progressive cluster dispersion was linked to declining Ca(2+) spark fidelity and magnitude, and slowed release kinetics from Ca(2+) propagation between more numerous RyR clusters. In healthy cells, this served to dampen the stimulatory actions of beta-adrenergic stimulation over the longer term and protect against pro-arrhythmic Ca(2+) waves. However, during HF, RyR dispersion was linked to impaired Ca(2+) release. Thus, RyR localization and function are intimately linked via channel phosphorylation by both CaMKII and PKA, which, while finely tuned in healthy cardiomyocytes, underlies impaired cardiac function during pathology. |
