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1. Activity-dependent endoplasmic reticulum Ca ²⁺ uptake depends on Kv2.1-mediated endoplasmic reticulum/plasma membrane junctions to promote synaptic transmission

   https://doi.org/10.1073/pnas.2117135119  

   Panzera, Lauren C.; Johnson, Ben; Quinn, Josiah A.; Cho, In Ha; Tamkun, Michael M.; Hoppa, Michael B. (July 2022, Proceedings of the National Academy of Sciences)

   The endoplasmic reticulum (ER) forms a continuous and dynamic network throughout a neuron, extending from dendrites to axon terminals, and axonal ER dysfunction is implicated in several neurological disorders. In addition, tight junctions between the ER and plasma membrane (PM) are formed by several molecules including Kv2 channels, but the cellular functions of many ER-PM junctions remain unknown. Recently, dynamic Ca 2+ uptake into the ER during electrical activity was shown to play an essential role in synaptic transmission. Our experiments demonstrate that Kv2.1 channels are necessary for enabling ER Ca 2+ uptake during electrical activity, as knockdown (KD) of Kv2.1 rendered both the somatic and axonal ER unable to accumulate Ca 2+ during electrical stimulation. Moreover, our experiments demonstrate that the loss of Kv2.1 in the axon impairs synaptic vesicle fusion during stimulation via a mechanism unrelated to voltage. Thus, our data demonstrate that a nonconducting role of Kv2.1 exists through its binding to the ER protein VAMP-associated protein (VAP), which couples ER Ca 2+ uptake with electrical activity. Our results further suggest that Kv2.1 has a critical function in neuronal cell biology for Ca 2+ handling independent of voltage and reveals a critical pathway for maintaining ER lumen Ca 2+ levels and efficient neurotransmitter release. Taken together, these findings reveal an essential nonclassical role for both Kv2.1 and the ER-PM junctions in synaptic transmission. 

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2. Tau regulates Arc stability in neuronal dendrites via a proteasome-sensitive but ubiquitin-independent pathway

   https://doi.org/10.1016/j.jbc.2024.107237  

   Yakout, Dina W; Shroff, Ankit; Wei, Wei; Thaker, Vishrut; Allen, Zachary D; Sajish, Mathew; Nazarko, Taras Y; Mabb, Angela M (May 2024, Journal of Biological Chemistry)

   DeMartino, George (Ed.)

   Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule-associated protein tau, a main component of neurofibrillary tangles. Alzheimer’s disease (AD) is the most common type of tauopathy and dementia, with amyloid-beta pathology as an additional hallmark feature of the disease. Besides its role in stabilizing microtubules, tau is localized at postsynaptic sites and can regulate synaptic plasticity. The activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that plays a key role in synaptic plasticity, learning, and memory. Arc has been implicated in AD pathogenesis and regulates the release of amyloid-beta. We found that decreased Arc levels correlate with AD status and disease severity. Importantly, Arc protein was upregulated in the hippocampus of Tau KO mice and dendrites of Tau KO primary hippocampal neurons. Overexpression of tau decreased Arc stability in an activity-dependent manner, exclusively in neuronal dendrites, which was coupled to an increase in the expression of dendritic and somatic surface GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. The tau-dependent decrease in Arc was found to be proteasome-sensitive, yet independent of Arc ubiquitination and required the endophilin-binding domain of Arc. Importantly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. These observations provide a potential molecular basis for synaptic dysfunction mediated through the accumulation of tau in dendrites. Our findings confirm that Arc is misregulated in AD and further show a physiological role for tau in regulating Arc stability and AMPA receptor targeting. 

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3. Chloroplast Stress Signals Orchestrate Epidermis‐Specific Remodeling of Mitochondria and ER Under High Light

   https://doi.org/10.1002/advs.202514970  

   Angelos, Evan R; Choi, Hee‐Seung; Guo, Jingzhe; Zanini, Andrea A; Burch‐Smith, Tessa M; Snyder, Emily; Part, Matthew; van_de_Ven, Wilhelmina; Hur, Manhoi; Balcke, Gerd Ulrich; et al (January 2026, Advanced Science)

   ABSTRACT Environmental stress demands precise coordination among organelles to maintain cellular homeostasis. InArabidopsis, high light (HL) exposure triggers chloroplast‐dependent remodeling of mitochondrial and endoplasmic reticulum (ER) morphology specifically in adaxial and abaxial epidermal cells, but not in mesophyll cells. Live‐cell imaging reveals that HL rapidly suppresses mitochondrial motility, followed by fusion‐driven elongation and ER cisternal expansion. Inhibition of photosynthetic, but not mitochondrial, electron transport abolishes these changes, confirming chloroplast activity as the upstream trigger. Pharmacological analyses show that exogenous H₂O₂induces mitochondrial elongation, whereas calcium chelation blocks both H₂O₂‐ and HL‐induced responses, demonstrating that chloroplast‐derived H₂O₂activates a Ca²⁺flux essential for remodeling. Proteomic and functional studies identify the Ca²⁺‐binding GTPase MIRO1 as a central integrator of this pathway. MIRO1 overexpression mimics HL‐induced morphodynamics, while mutations disrupting its Ca²⁺‐binding or acetylation motifs abolish the response, establishing Ca²⁺‐dependent MIRO1 activity as a prerequisite for remodeling. Together, these findings reveal an epidermis‐specific, light‐responsive network in which chloroplast‐derived H₂O₂initiates Ca²⁺signaling through MIRO1 to coordinate mitochondrial and ER remodeling—a spatially restricted mechanism of organellar communication and stress adaptation at the plant–environment interface. 

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4. Postsynaptic Calcium Extrusion at the Mouse Neuromuscular Junction Alkalinizes the Synaptic Cleft

   https://doi.org/10.1523/JNEUROSCI.0815-23.2023  

   Durbin, Ryan J.; Heredia, Dante J.; Gould, Thomas W.; Renden, Robert B. (August 2023, The Journal of Neuroscience)

   Neurotransmission is shaped by extracellular pH. Alkalization enhances pH-sensitive transmitter release and receptor activation, whereas acidification inhibits these processes and can activate acid-sensitive conductances in the synaptic cleft. Previous work has shown that the synaptic cleft can either acidify because of synaptic vesicular release and/or alkalize because of Ca²⁺extrusion by the plasma membrane ATPase (PMCA). The direction of change differs across synapse types. At the mammalian neuromuscular junction (NMJ), the direction and magnitude of pH transients in the synaptic cleft during transmission remain ambiguous. We set out to elucidate the extracellular pH transients that occur at this cholinergic synapse under near-physiological conditions and identify their sources. We monitored pH-dependent changes in the synaptic cleft of the mouse levator auris longus using viral expression of the pseudoratiometric probe pHusion-Ex in the muscle. Using mice from both sexes, a significant and prolonged alkalization occurred when stimulating the connected nerve for 5 s at 50 Hz, which was dependent on postsynaptic intracellular Ca²⁺release. Sustained stimulation for a longer duration (20 s at 50 Hz) caused additional prolonged net acidification at the cleft. To investigate the mechanism underlying cleft alkalization, we used muscle-expressed GCaMP3 to monitor the contribution of postsynaptic Ca²⁺. Activity-induced liberation of intracellular Ca²⁺in muscle positively correlated with alkalization of the synaptic cleft, whereas inhibiting PMCA significantly decreased the extent of cleft alkalization. Thus, cholinergic synapses of the mouse NMJ typically alkalize because of cytosolic Ca²⁺liberated in muscle during activity, unless under highly strenuous conditions where acidification predominates. 

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5. Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and Alzheimer’s disease

   https://doi.org/10.1073/pnas.2301534120  

   Niere, Farr; Uneri, Ayse; McArdle, Colin J.; Deng, Zhiyong; Egido-Betancourt, Hailey X.; Cacheaux, Luisa P.; Namjoshi, Sanjeev V.; Taylor, William C.; Wang, Xin; Barth, Samuel H.; et al (November 2023, Proceedings of the National Academy of Sciences)

   L-type voltage-gated calcium (Ca²⁺) channels (L-VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown whether molecular mechanisms leading to disrupted L-VGCC across neurodegenerative disorders are conserved. Importantly, L-VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L-VGCC channel density and subcellular compartmentalization are understudied. Herein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L-VGCC activity are associated with increased expression of the RNA-binding protein (RBP) Parkinsonism-associated deglycase (DJ-1). DJ-1 binds the mRNA coding for the alpha and auxiliary Ca²⁺channel subunits Ca_V1.2 and α2δ2, and represses their mRNA translation, only in the disease states, specifically preclinical models of tuberous sclerosis complex (TSC) and Alzheimer’s disease (AD). In agreement, DJ-1-mediated repression of Ca_V1.2/α2δ2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L-VGCC calcium activity. Finding of DJ-1-regulated L-VGCC activity in dendrites in TSC and AD provides a unique signaling pathway that can be targeted in clinical mTORopathies. 

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