Dataset Information

Spine-to-Dendrite Calcium Modeling Discloses Relevance for Precise Positioning of Ryanodine Receptor-Containing Spine Endoplasmic Reticulum.

ABSTRACT: The endoplasmic reticulum (ER) forms a complex endomembrane network that reaches into the cellular compartments of a neuron, including dendritic spines. Recent work discloses that the spine ER is a dynamic structure that enters and leaves spines. While evidence exists that ER Ca²⁺ release is involved in synaptic plasticity, the role of spine ER morphology remains unknown. Combining a new 3D spine generator with 3D Ca²⁺ modeling, we addressed the relevance of ER positioning on spine-to-dendrite Ca²⁺ signaling. Our simulations, which account for Ca²⁺ exchange on the plasma membrane and ER, show that spine ER needs to be present in distinct morphological conformations in order to overcome a barrier between the spine and dendritic shaft. We demonstrate that RyR-carrying spine ER promotes spine-to-dendrite Ca²⁺ signals in a position-dependent manner. Our simulations indicate that RyR-carrying ER can initiate time-delayed Ca²⁺ reverberation, depending on the precise position of the spine ER. Upon spine growth, structural reorganization of the ER restores spine-to-dendrite Ca²⁺ communication, while maintaining aspects of Ca²⁺ homeostasis in the spine head. Our work emphasizes the relevance of precise positioning of RyR-containing spine ER in regulating the strength and timing of spine Ca²⁺ signaling, which could play an important role in tuning spine-to-dendrite Ca²⁺ communication and homeostasis.

SUBMITTER: Breit M

PROVIDER: S-EPMC6199256 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Spine-to-Dendrite Calcium Modeling Discloses Relevance for Precise Positioning of Ryanodine Receptor-Containing Spine Endoplasmic Reticulum.

Breit Markus M Kessler Marcus M Stepniewski Martin M Vlachos Andreas A Queisser Gillian G

Scientific reports 20181023 1

The endoplasmic reticulum (ER) forms a complex endomembrane network that reaches into the cellular compartments of a neuron, including dendritic spines. Recent work discloses that the spine ER is a dynamic structure that enters and leaves spines. While evidence exists that ER Ca<sup>2+</sup> release is involved in synaptic plasticity, the role of spine ER morphology remains unknown. Combining a new 3D spine generator with 3D Ca<sup>2+</sup> modeling, we addressed the relevance of ER positioning ...[more]

PMID: 30353066

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Project description:Essential Tremor (ET) is a prevalent neurological disease characterized by an 8-10 Hz action tremor. Molecular mechanisms of ET remain poorly understood. Clinical data suggest the importance of the cerebellum in disease pathophysiology, and pathological studies indicate Purkinje Cells (PCs) incur damage. Our recent cerebellar cortex and PC-specific transcriptome studies identified alterations in calcium (Ca2+) signaling pathways that included ryanodine receptor type 1 (RyR1) in ET. RyR1 is an intracellular Ca2+ release channel located on the Endoplasmic Reticulum (ER), and in cerebellum is predominantly expressed in PCs. Under stress conditions, RyR1 undergoes several post-translational modifications (protein kinase A [PKA] phosphorylation, oxidation, nitrosylation), coupled with depletion of the channel-stabilizing binding partner calstabin1, which collectively characterize a "leaky channel" biochemical signature. In this study, we found markedly increased PKA phosphorylation at the RyR1-S2844 site, increased RyR1 oxidation and nitrosylation, and calstabin1 depletion from the RyR1 complex in postmortem ET cerebellum. Decreased calstabin1-RyR1-binding affinity correlated with loss of PCs and climbing fiber-PC synapses in ET. This 'leaky' RyR1 signature was not seen in control or Parkinson's disease cerebellum. Microsomes from postmortem cerebellum demonstrated excessive ER Ca2+ leak in ET vs. controls, attenuated by channel stabilization. We further studied the role of RyR1 in tremor using a mouse model harboring a RyR1 point mutation that mimics constitutive site-specific PKA phosphorylation (RyR1-S2844D). RyR1-S2844D homozygous mice develop a 10 Hz action tremor and robust abnormal oscillatory activity in cerebellar physiological recordings. Intra-cerebellar microinfusion of RyR1 agonist or antagonist, respectively, increased or decreased tremor amplitude in RyR1-S2844D mice, supporting a direct role of cerebellar RyR1 leakiness for tremor generation. Treating RyR1-S2844D mice with a novel RyR1 channel-stabilizing compound, Rycal, effectively dampened cerebellar oscillatory activity, suppressed tremor, and normalized cerebellar RyR1-calstabin1 binding. These data collectively support that stress-associated ER Ca2+ leak via RyR1 may contribute to tremor pathophysiology.

Dataset Information

Spine-to-Dendrite Calcium Modeling Discloses Relevance for Precise Positioning of Ryanodine Receptor-Containing Spine Endoplasmic Reticulum.

Publications

Spine-to-Dendrite Calcium Modeling Discloses Relevance for Precise Positioning of Ryanodine Receptor-Containing Spine Endoplasmic Reticulum.

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