Biology subjects

Shi, Y. S.

Publications and source records attributed to Shi, Y. S..

6 recordsLinked to original sources

bioRxiv2026

Ventricular Expansion Couples Hyperosmotic Stress to Thirst

Thirst is thought to arise from osmotic signals detected by circumventricular organs, yet how hyperosmotic stress activates mechanosensitive channels remains unclear because cell shrinkage should reduce membrane tension. Here we identify a brain-scale mechanical signal that couples systemic osmotic stress to drinking. In mice, hypertonic saline rapidly increased serum and cerebrospinal fluid osmolality, expanded the lateral ventricles, and promoted water intake. Relieving or blocking ventricular deformation attenuated drinking without eliminating osmotic gradients. Hyperosmotic challenge also produced localized deformation of periventricular cells, where spatial transcriptomics revealed candidate mechanosensitive channels, including Tmem63b and Piezo1. Thus, ventricular expansion provides a mechanical component of osmotic thirst, uncovering an osmo-mechanical layer of interoceptive regulation.

neuroscience↗

bioRxiv2025

Conditional deletion of Tmem63b does not impact mouse voiding behavior

The proper function of the lower urinary tract depends on its ability to sense and react to mechanical forces as urine is produced, transported, stored, and eliminated; however, our current understanding of the mechanosensors involved in these events is limited. TMEM63 ion channels are reported to function as mechanosensors/osmosensors in other organs, and our studies revealed that the primary site of Tmem63a and Tmem63b gene expression and TMEM63B protein expression in the mouse bladder wall was the urothelium. Despite this localization, voiding behavior in conditional urothelial Tmem63b knockout mice, assessed using a video-monitored void-spot screening assay, was not significantly different from control mice, even when the urothelium was stressed by exposure to cyclophosphamide. We further observed that dorsal root ganglia sensory neurons, including those innervating the bladder, were also sites of Tmem63a, Tmem63b, and TMEM63B expression. Again, voiding behavior was not impacted in conditional sensory neuron Tmem63b knockout mice, treated or not with cyclophosphamide. Our studies reveal that the urothelium and dorsal root ganglia are sites of Tmem63a, Tmem63b, and TMEM63B expression, but deletion of Tmem63b alone in these tissues does not result in a demonstrable voiding phenotype.

physiology↗

bioRxiv2024

α/β-Hydrolase domain-containing 6 (ABHD6) accelerates the desensitization and deactivation of TARP γ-2-containing AMPA receptors

AMPA receptors (AMPARs) mediate most of the fast excitatory synaptic transmission in the mammalian brain. Their efficacy in responding to presynaptic glutamate release depends on their kinetics, which are determined by AMPARs and their auxiliary subunit composition. /{beta}-Hydrolase domain-containing 6 (ABHD6) is an AMPAR auxiliary subunit that has been shown to negatively regulate the surface delivery of AMPARs and AMPAR-mediated currents. Overexpression of ABHD6 has been shown to decrease the rising slope and increase the decay {tau} of mEPSCs. However, whether ABHD6 is involved in regulating AMPAR kinetics remains unclear. Here, we found that ABHD6 itself had no effect on the gating kinetics of GluA1 and GluA2(Q) containing homomeric receptors. However, in the presence of the auxiliary subunit TARP {gamma}-2, ABHD6 accelerated the deactivation and desensitization of both GluA1 and GluA2(Q) containing homomeric receptors independent of their splicing isoforms (flip and flop) and the editing isoforms of GluA2 (R or G at position 764), except for the deactivation of GluA2(Q)i-G isoform. Besides, the recovery from desensitization of GluA1 with flip splicing isoform was slowed by the co-expression of ABHD6 in the presence of TARP {gamma}-2. Furthermore, ABHD6 accelerated the deactivation and desensitization of GluA1i/GluA2(R)i-G and GluA2(R)i-G/GluA3(R)i heteromeric receptors in the presence of TARP {gamma}-2. We also found that ABHD6-knockout neurons displayed slower deactivation and desensitization. Therefore, these results demonstrate that ABHD6 regulates AMPAR gating kinetics in a TARP {gamma}-2-dependent manner. SIGNIFICANCE STATEMENTThe efficacy of AMPARs in responding to presynaptic glutamate release depends on their kinetics, including deactivation, desensitization, and recovery from desensitization, which are determined by AMPARs and their auxiliary subunit composition. Using ultra-fast application of glutamate and outside-out patch recordings, we found that, in the presence of the auxiliary subunit TARP {gamma}-2, ABHD6 accelerated the deactivation and desensitization of GluA1i/GluA2(R)i-G and GluA2(R)i-G/GluA3(R)i heteromeric receptors and GluA1 and GluA2(Q) containing homomeric receptors independent of their splicing isoforms (flip and flop) and the editing isoforms of GluA2 (R or G at position 764), except for the deactivation of GluA2(Q)i-G isoform. In ABHD6 knockout neurons, we also observed slower deactivation and desensitization. These results demonstrated that ABHD6 regulates AMPAR gating kinetics in a TARP {gamma}-2-dependent manner.

neuroscience↗

bioRxiv2024

Functional imaging of whole mouse embryonic development in utero

Despite significant advances in structural and genetic studies, investigations of early embryonic functions, such as brain activity, have long been constrained by technical challenges. Functional ultrasound (fUS) has emerged as a breakthrough modality, enabling real-time monitoring of brain activity with exceptional spatial and temporal resolution and offering unprecedented opportunities for studying functional embryonic development. In this study, we used fUS to monitor whole-embryo activity in mice from embryonic days E8.5 to E18.5, revealing patterns of neural activity throughout embryogenesis. This approach provides new opportunities to explore brain development dynamically as it unfolds. Moreover, we observed embryo responses to external stimuli, including sound, in both mice and cynomolgus macaques, offering insights into early sensory processing and neural maturation. In summary, our study establishes fUS as a powerful tool for studying embryonic brain functional development, with significant implications for scientific research, especially in non- human primate models, and clinical applications.

developmental biology↗

bioRxiv2023

Cryo-EM structure of TMEM63C suggests it functions as a monomer

The TMEM63 family proteins (A, B, and C), calcium-permeable channels in animals that are preferentially activated by hypo-osmolality, have been implicated in various physiological functions. Deficiency of these channels would cause many diseases including hearing loss. However, their structures and physiological roles are not yet well understood. In this study, we determined the cryo-EM structure of the mouse TMEM63C at 3.56 [A], and revealed structural differences compared to its plant orthologues OSCAs. Further structural guided mutagenesis and electrophysiological studies demonstrated the important roles of the coupling of TM0 and TM6 in channel activity. Additionally, we confirmed that the physiological state of TMEM63C is monomer, while TMEM63B is a mix of monomer and dimer in cells, suggesting that oligomerization is a novel regulatory mechanism for TMEM63 proteins.

biophysics↗

bioRxiv2020

Endophilin A1 promotes Actin Polymerization in response to Ca2+/calmodulin to Initiate Structural Plasticity of Dendritic Spines

Dendritic spines of excitatory neurons undergo activity-dependent structural and functional plasticity, which are cellular correlates of learning and memory. However, mechanisms underlying the rapid morphological changes immediately after NMDAR-mediated Ca2+ influx into spines remain poorly understood. Here we report that endophilin A1, a neuronal N-BAR protein, orchestrates membrane dynamics with actin polymerization to initiate spine enlargement in the induction phase of long-term potentiation (LTP). Upon LTP induction, Ca2+/calmodulin enhances its binding to both membrane and p140Cap, a cytoskeleton regulator. As a result, endophilin A1 rapidly associates with the relaxed plasma membrane and promotes actin polymerization, leading to acute expansion of spine head. Moreover, not only the p140Cap-binding, but also calmodulin- and membrane-binding capacities of endophilin A1 are required for LTP and long-term memory. Thus, endophilin A1 functions as calmodulin effector to drive spine enlargement in response to Ca2+ influx in the initial phase of structural plasticity.

cell biology↗