https://scholar.dgist.ac.kr/handle/20.500.11750/730 Tue, 27 Oct 2026 05:14:53 GMT 2026-10-27T05:14:53Z https://scholar.dgist.ac.kr/handle/20.500.11750/60967 Title: Structural rigidity of the I-II loop couples CaV β anchoring to CaV2.2 gating modes Author(s): Woo, Jin-Nyeong; Kim, Jung-Eun; Suh, Byung-Chang Abstract: The auxiliary beta subunits of voltage-gated Ca2+ (Ca-V) channels are fundamental regulators of channel gating and neuronal excitability. While the subcellular localization of beta subunits is known to influence current density and inactivation, the precise kinetic mechanism by which they differentially modulate channel opening and closing remains elusive. Here, we report a kinetic paradox in Ca(V)2.2 channels: membrane-anchored beta subunits decelerate current decay during depolarization yet accelerate tail deactivation upon repolarization, whereas cytosolic beta subunits promote rapid decay but prolong deactivation. Using quantitative kinetic analysis and Markov state modeling, we demonstrate that macroscopic current decay is not solely a monolithic irreversible inactivation process but a composite of irreversible inactivation and a reversible transition to a nonconducting state. We reveal that membrane-anchored beta subunits suppress the transition to this reversible nonconducting state, thereby maintaining the open state, while facilitating a rapid return from the nonconducting state to prevent kinetic trapping. Furthermore, by manipulating the linker length of beta subunits and engineering the I-II loop hinge region (R370), we identify that the physical proximity of the beta subunit to the plasma membrane, coupled with the structural rigidity of the I-II loop, acts as a mechanical determinant that governs this gating pathway selection. Our findings provide a unified gating model in which the beta subunit fine-tunes the dynamic equilibrium between conducting and nonconducting states via mechanical constraint on the channel complex, offering a comprehensive resolution to the distinct regulation of Ca(V)2.2 kinetics. Tue, 30 Jun 2026 15:00:00 GMT https://scholar.dgist.ac.kr/handle/20.500.11750/60967 2026-06-30T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/60886 Title: TMEM16E-mediated macropinocytosis promotes cell survival under acidic stress Author(s): Kim, Jung-Eun; Lee, Byoung-Cheol; Suh, Byung-Chang Abstract: TMEM16E is a transmembrane protein that functions both as a phospholipid scramblase and a non-selective ion channel, playing a critical role in cellular ion transport and membrane dynamics. Recent studies have shown that the TMEM16E scramblase also facilitates membrane internalization through macropinocytosis. This study investigates the effects of extracellular protons on TMEM16E's scrambling activity and subsequent macropinocytosis under acidic conditions, which are particularly relevant in pathophysiological contexts such as muscular dystrophies and cancers. Our results indicate that TMEM16E-induced macropinocytosis, as evidenced by the internalization of annexin V, is significantly enhanced in acidic environments (pH 5.5). However, the overall number of macropinosomes, assessed using 70 kDa dextran, remained unchanged despite variations in extracellular pH. This suggests that TMEM16E-mediated macropinocytosis operates independently of extracellular proton concentrations. Upon extracellular acidification, both TMEM16E scrambling activity and macropinocytosis were rapidly inhibited, leading to a swift decrease in intracellular Ca2+ levels compared to physiological conditions. Notably, intracellular Ca2+ was cleared more quickly in acidic environments, indicating a regulatory role for the proton-dependent Ca2+ clearance pathways. Using wound healing and MTS assays, we demonstrated that TMEM16E expression significantly enhances cell proliferation and survival under acidic conditions. Our findings underscore the importance of TMEM16E-mediated macropinocytosis in maintaining plasma membrane integrity and promoting cell survival, highlighting its role as a crucial signaling pathway in both physiological and pathological contexts. Sun, 31 May 2026 15:00:00 GMT https://scholar.dgist.ac.kr/handle/20.500.11750/60886 2026-05-31T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/60877 Title: TWIK-1 plays distinct roles in spinal and peripheral sensory circuits controlling mechanical sensitivity and neuropathic hypersensitivity Author(s): Seo Young Yang; Tery Yun; Yunjeong Lee; Jae Hyuk Jeon; Seojung Kim; Eun Yeong Lim; Junhee Park; Kim, Yong Geon; Jonghoon Jung; Woo, Jin-Nyeong; Yan Zhang; Hyeonwi Son; John Shannonhouse; Juhyun Kim; Eunsil Cho; Young Hoon Sung; Eun-Mi Hwang; Byung-Chang Suh; Pojeong Park; Mi-Ryoung Song; Myungin Baek; Jaekwang Lee; Yu Shin Kim; Jae-Yong Park; Hyosang Lee Abstract: Ion channels are essential for sensing somatic stimuli, and their dysregulation can cause chronic conditions such as neuropathic pain. Although the potassium channel Twik-1 has been linked to sensory processing, its specific roles in the somatosensory system under normal and disease conditions remain unclear. Here, we demonstrate that systemic deletion of Twik-1 selectively reduces innocuous tactile and noxious mechanosensation evoked by both static and dynamic mechanical stimuli and facilitates recovery from mechanical hypersensitivity after peripheral nerve injury. Conditional deletion of Twik-1 in spinal cord neurons, pan-inhibitory neurons, or spinal inhibitory interneurons consistently disrupts innocuous tactile and noxious mechanical sensitivity, while sparing responses to high-intensity mechanical stimulation as well as noxious heat and cold. Notably, these manipulations do not affect nerve injury-induced mechanical hypersensitivity. In contrast, selective deletion of Twik-1 in dorsal root ganglion (DRG) neurons preserves baseline somatosensory and nociceptive functions, including innocuous tactile and noxious mechanical sensitivity, but impairs the persistence of mechanical hypersensitivity after nerve injury. This reduction in hypersensitivity is accompanied by decreased aberrant excitability in injured DRG neurons and distinct transcriptional changes. Together, these results suggest that Twik-1 facilitates innocuous tactile and noxious mechanosensation through spinal inhibitory circuits under baseline conditions, while supporting the maintenance of neuropathic pain via its functions in primary sensory neurons. Sun, 31 May 2026 15:00:00 GMT https://scholar.dgist.ac.kr/handle/20.500.11750/60877 2026-05-31T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/60851 Title: Heat-and PIP2-dependent TRPM4 activity underlies mutually exclusive human diseases Author(s): Tian, Yuhua; Bae, Soohyeon; Wu, Xuesong; Rouen, Kyle C.; Hernández-Gonzalez, Adriana; Han, Yanxiao; Tekreeti, Abdullah Al; Vu, Simon; Chen, Irene; Li, Ellen; Vorobyov, Igor; Yarov-Yarovoy, Vladimir; Suh, Byung-Chang; Hwang, Samuel T.; Zheng, Jie Abstract: Temperature-sensitive transient receptor potential melastatin subfamily 4 (TRPM4) ion channels convert intracellular calcium increases into membrane depolarization, thereby linking these two powerful cellular signaling pathways in diverse physiological processes. TRPM4 mutations cause severe human hereditary cardiovascular and skin diseases; mysteriously, while these mutations are gain-of-function in nature, they affect the heart and the skin in a mutually exclusive manner. Here, we show that phosphatidylinositol 4,5-bisphosphate (PIP2) lipid is a required cofactor for TRPM4 activity by tightly regulating its calcium sensitivity. We detected two PIP2 binding sites and located the high-affinity site adjacent to the S4-S5 linker. We demonstrated that skin disease-associated TRPM4 mutations relieve the tight control of PIP2, resulting in elevated channel activity but only at the body surface temperature. In contrast, heart diseases are associated with mutations known to boost the number of channels, an effect we found to be annihilated by channel desensitization outside the body core. Indeed, dendritic cells from transgenic mice carrying a skin disease mutant exhibited elevated migration at 25-to-30 degrees C range compared to those from normal mice, but no difference was observed at 37 degrees C. These findings shed light on a molecular mechanism for dynamic regulation of cellular signaling in physiology and diseases. Tue, 31 Mar 2026 15:00:00 GMT https://scholar.dgist.ac.kr/handle/20.500.11750/60851 2026-03-31T15:00:00Z