Alpha-synuclein oligomers mediate an aberrant form of spike-induced calcium release from IP3 receptor via the association with calcium binding protein 1

ABSTRACT The sarcoplasmic reticulum (SR) plays a critical role in excitation-contraction coupling by regulating the cytoplasmic calcium concentration of striated muscle. The histidine-rich calcium-binding protein (HRCBP) is expressed in the junctional SR, the site of calcium release from the SR. HRCBP is expressed exclusively in muscle tissues and binds calcium with low affinity and high capacity. In addition, HRCBP interacts with triadin, a protein associated with the ryanodine receptor and thought to be involved in calcium release. Its calcium binding properties, localization to the SR, and interaction with triadin suggest that HRCBP is involved in calcium handling by the SR. To determine the function of HRCBP in vivo, we inactivated HRC, the gene encoding HRCBP, in mice. HRC knockout mice exhibited impaired weight gain beginning at 11 months of age, which was marked by reduced skeletal muscle and fat mass, and triadin protein expression was upregulated in the heart of HRC knockout mice. In addition, HRC null mice displayed a significantly exaggerated response to the induction of cardiac hypertrophy by isoproterenol compared to their wild-type littermates. The exaggerated response of HRC knockout mice to the induction of cardiac hypertrophy is consistent with a regulatory role for HRCBP in calcium handling in vivo and suggests that mutations in HRC, in combination with other genetic or environmental factors, might contribute to pathological hypertrophy and heart failure.

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Calcium release from rod outer segments: Evidence for a cGMP-sensitive calcium binding protein

Biochemical and Biophysical Research Communications ◽

10.1016/0006-291x(91)90891-a ◽

1991 ◽

Vol 176 (1) ◽

pp. 70-78

Author(s):

James J. Devenny ◽

James W. Clack

Keyword(s):

Calcium Binding ◽

Calcium Release ◽

Binding Protein ◽

Calcium Binding Protein ◽

Rod Outer Segments ◽

Outer Segments

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α-Synuclein oligomers mediate the aberrant form of spike-induced calcium release from IP3 receptor

Scientific Reports ◽

10.1038/s41598-019-52135-3 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Kenji Yamamoto ◽

Yasuhiko Izumi ◽

Monami Arifuku ◽

Toshiaki Kume ◽

Hideyuki Sawada

Keyword(s):

Calcium Binding ◽

Calcium Release ◽

Pyramidal Neurons ◽

Lewy Body Disease ◽

Higher Order ◽

Ip3 Receptor ◽

Central Neurons ◽

Type K ◽

Dependent Inactivation ◽

Aberrant Form

Abstract Emerging evidence implicates α-synuclein oligomers as potential culprits in the pathogenesis of Lewy body disease (LBD). Soluble oligomeric α-synuclein accumulation in cytoplasm is believed to modify neuronal activities and intraneural Ca2+ dynamics, which augment the metabolic burden in central neurons vulnerable to LBD, although this hypothesis remains to be fully tested. We evaluated how intracellular α-synuclein oligomers affect the neuronal excitabilities and Ca2+ dynamics of pyramidal neurons in neocortical slices from mice. Intracellular application of α-synuclein containing stable higher-order oligomers (αSNo) significantly reduced spike frequency during current injection, elongated the duration of spike afterhyperpolarization (AHP), and enlarged AHP current charge in comparison with that of α-synuclein without higher-order oligomers. This αSNo-mediated alteration was triggered by spike-induced Ca2+ release from inositol trisphosphate receptors (IP3R) functionally coupled with L-type Ca2+ channels and SK-type K+ channels. Further electrophysiological and immunochemical observations revealed that α-synuclein oligomers greater than 100 kDa were directly associated with calcium-binding protein 1, which is responsible for regulating IP3R gating. They also block Ca2+-dependent inactivation of IP3R, and trigger Ca2+-induced Ca2+ release from IP3R during multiple spikes. This aberrant machinery may result in intraneural Ca2+ dyshomeostasis and may be the molecular basis for the vulnerability of neurons in LBD brains.

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