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1. Ca ²⁺ release or Ca ²⁺ entry, that is the question: what governs Ca ²⁺ oscillations in pancreatic β cells?

   https://doi.org/10.1152/ajpendo.00030.2023  

   Fletcher, Patrick A.; Thompson, Ben; Liu, Chanté; Bertram, Richard; Satin, Leslie S.; Sherman, Arthur S. (June 2023, American Journal of Physiology-Endocrinology and Metabolism)

   The standard model for Ca 2+ oscillations in insulin-secreting pancreatic β cells centers on Ca 2+ entry through voltage-activated Ca 2+ channels. These work in combination with ATP-dependent K + channels, which are the bridge between the metabolic state of the cells and plasma membrane potential. This partnership underlies the ability of the β cells to secrete insulin appropriately on a minute-to-minute time scale to control whole body plasma glucose. Though this model, developed over more than 40 years through many cycles of experimentation and mathematical modeling, has been very successful, it has been challenged by a hypothesis that calcium-induced calcium release from the endoplasmic reticulum through ryanodine or inositol trisphosphate (IP3) receptors is instead the key driver of islet oscillations. We show here that the alternative model is in fact incompatible with a large body of established experimental data and that the new observations offered in support of it can be better explained by the standard model. 

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2. Phosphatidylserine affinity for and flip-flop dependence on Ca ²⁺ and Mg ²⁺ ions

   https://doi.org/10.1039/d4fd00206g  

   Hymas, Preston P; Conboy, John C (January 2025, Faraday Discussions)

   Ca²⁺ions are believed to play a crucial role in enzymatic regulation of lipid membrane asymmetry, yet direct effects of Ca²⁺on lipid flip-flop are unknown. Present work examines the influence of Ca–lipid interactions on lipid translocation. 

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3. A model of cardiac ryanodine receptor gating predicts experimental Ca ²⁺ -dynamics and Ca ²⁺ -triggered arrhythmia in the long QT syndrome

   https://doi.org/10.1063/1.5000711  

   Wilson, Dan; Ermentrout, Bard; Němec, Jan; Salama, Guy (September 2017, Chaos: An Interdisciplinary Journal of Nonlinear Science)
4. Phosphatidylinositol 3, 5‐bisphosphate regulates Ca ²⁺ transport during yeast vacuolar fusion through the Ca ²⁺ ATPase Pmc1

   https://doi.org/10.1111/tra.12736  

   Miner, Gregory E.; Sullivan, Katherine D.; Zhang, Chi; Rivera‐Kohr, David; Guo, Annie; Hurst, Logan R.; Ellis, Ez C.; Starr, Matthew L.; Jones, Brandon C.; Fratti, Rutilio A. (June 2020, Traffic)

   Abstract The transport of Ca²⁺across membranes precedes the fusion and fission of various lipid bilayers. Yeast vacuoles under hyperosmotic stress become fragmented through fission events that requires the release of Ca²⁺stores through the TRP channel Yvc1. This requires the phosphorylation of phosphatidylinositol‐3‐phosphate (PI3P) by the PI3P‐5‐kinase Fab1 to produce transient PI(3,5)P₂pools. Ca²⁺is also released during vacuole fusion upontrans‐SNARE complex assembly, however, its role remains unclear. The effect of PI(3,5)P₂on Ca²⁺flux during fusion was independent of Yvc1. Here, we show that while low levels of PI(3,5)P₂were required for Ca²⁺uptake into the vacuole, increased concentrations abolished Ca²⁺efflux. This was as shown by the addition of exogenous dioctanoyl PI(3,5)P₂or increased endogenous production of by the hyperactivefab1^T2250Amutant. In contrast, the lack of PI(3,5)P₂on vacuoles from the kinase deadfab1^EEEmutant showed delayed and decreased Ca²⁺uptake. The effects of PI(3,5)P₂were linked to the Ca²⁺pump Pmc1, as its deletion rendered vacuoles resistant to the effects of excess PI(3,5)P₂. Experiments with Verapamil inhibited Ca²⁺uptake when added at the start of the assay, while adding it after Ca²⁺had been taken up resulted in the rapid expulsion of Ca²⁺. Vacuoles lacking both Pmc1 and the H⁺/Ca²⁺exchanger Vcx1 lacked the ability to take up Ca²⁺and instead expelled it upon the addition of ATP. Together these data suggest that a balance of efflux and uptake compete during the fusion pathway and that the levels of PI(3,5)P₂can modulate which path predominates. 

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5. Design of a light and Ca ²⁺ switchable organic–peptide hybrid

   https://doi.org/10.1073/pnas.2411316122  

   Khaleel, Zinah_Hilal; No, Young_Hyun; Kim, Nam_Hyeong; Bae, Do_Hyun; Wu, Yibing; Kim, Suhyeon; Choi, Hojae; Lee, Da_Eun; Jeong, Se_Yun; Ko, Yoon-Joo; et al (January 2025, Proceedings of the National Academy of Sciences)

   The design of organic–peptide hybrids has the potential to combine our vast knowledge of protein design with small molecule engineering to create hybrid structures with complex functions. Here, we describe the computational design of a photoswitchable Ca²⁺-binding organic–peptide hybrid. The designed molecule, designated Ca²⁺-binding switch (CaBS), combines an EF-hand motif from classical Ca²⁺-binding proteins such as calmodulin with a photoswitchable group that can be reversibly isomerized between a spiropyran (SP) and merocyanine (MC) state in response to different wavelengths of light. The MC/SP group acts both as a photoswitch as well as an optical sensor of Ca²⁺binding. Photoconversion of the SP to the corresponding MC unmasks an acidic phenol, which CaBS uses as an integral part of both its Ca²⁺-binding site as well as its tertiary and quaternary structure. By design, the SP state of CaBS is monomeric, while the Ca²⁺-bound form of the MC state is an obligate dimer, with two Ca²⁺-binding sites formed at the interface of a domain-swapped dimer. Thus, light and Ca²⁺were expected to serve as an “AND gate” that powers a change in backbone structure/dynamics, oligomerization state, and fluorescence properties of the designed molecule. CaBS was designed using Rosetta and molecular dynamics simulations, and experimentally characterized by nuclear magnetic resonance, isothermal titration calorimetry, and optical titrations. These data illustrate the potential of combining small molecule engineering with de novo protein design to develop sensors whose conformation, association state, and optical properties respond to multiple environmental cues. 

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