Cell calcium最新文献

The central nervous system (CNS) is constantly surveilled by microglia, highly motile and dynamic cells deputed to act as the first line of immune defense in the brain and spinal cord. Alterations in the homeostasis of the CNS are detected by microglia that respond by extending their processes or – following major injuries – by migrating toward the affected area. Understanding the mechanisms controlling directed cell migration of microglia is crucial to dissect their responses to neuroinflammation and injury. We used a combination of pharmacological and genetic approaches to explore the involvement of calcium (Ca²⁺) signaling in the directed migration of human induced pluripotent stem cell (iPSC)-derived microglia challenged with a purinergic stimulus. This approach mimics cues originating from injury of the CNS. Unexpectedly, simultaneous imaging of microglia migration and intracellular Ca²⁺ changes revealed that this phenomenon does not require Ca²⁺ signals generated from the endoplasmic reticulum (ER) and store-operated Ca²⁺ entry (SOCE) pathways. Instead, we find evidence that human microglial chemotaxis to purinergic signals is mediated by cyclic AMP in a Ca²⁺-independent manner. These results challenge prevailing notions, with important implications in neurological conditions characterized by perturbation in Ca²⁺ homeostasis.

Two recent papers have highlighted that STIM1, a key component of Store-operated Ca2+-entry, is able to translocate to the nucleus and participate in nuclear Ca²⁺-handling and in DNA repair. These finding opens new avenues on the role that this Ca²⁺-sensing protein may have in health and disease.

The non-selective cation channel TRPC1 is highly expressed in the brain. Recent research shows that neuronal TRPC1 forms heteromeric complexes with TRPC4 and TRPC5, with a small portion existing as homotetramers, primarily in the ER. Given that most studies have focused on the role of heteromeric TRPC1/4/5 complexes, it is crucial to investigate the specific role of homomeric TRPC1 in maintaining brain homeostasis. This review highlights recent findings on TRPC1 in the brain, with a focus on the hippocampus, and compiles the latest data on modulators and their binding sites within the TRPC1/4/5 subfamily to stimulate new research on more selective TRPC1 ligands.

Transient receptor potential canonical 3 (TRPC3) is a calcium-permeable, non-selective cation channel known to be regulated by components of the phospholipase C (PLC)-mediated signaling pathway, such as Ca²⁺, diacylglycerol (DAG) and phosphatidylinositol 4,5-biphosphate (PI(4,5)P₂). However, the molecular gating mechanism by these regulators is not yet fully understood, especially its regulation by PI(4,5)P₂, despite the importance of this channel in cardiovascular pathophysiology. Recently, Clarke et al. (2024) have reported that PI(4,5)P₂ is a positive modulator for TRPC3 using molecular dynamics simulations and patch-clamp techniques. They have demonstrated a multistep gating mechanism of TRPC3 with the binding of PI(4,5)P₂ to the lipid binding site located at the pre-S1/S1 nexus, and the propagation of PI(4,5)P₂ sensing to the pore domain via a salt bridge between the TRP helix and the S4–S5 linker.

Aberrant Ca²⁺ signaling is an early hallmark of multiple neurodegenerative syndromes including Alzheimer's and Parkinson's disease (AD and PD) as well as classes of rare genetic disorders such as Spinocebellar Ataxias. Therapeutic strategies that target aberrant Ca²⁺ signals whilst allowing normal neuronal Ca²⁺ signals have been a challenge. In a recent study Princen et al., performed a screen in the tauP301L cell model of AD for drugs that could specifically ameliorate the excess Ca²⁺ entry observed. They identified a class of compounds referred to as ReS19-T that interact with Septins, previously identified as regulators of the Store-operated Ca²⁺ entry channel Orai. Drug treatment of the cellular model, a mouse model and human iPSC derived neurons alleviate cellular and systemic deficits associated with tauP301L. Comparison of Septin filament architecture in disease conditions with and without the drug treatment indicate that excess Ca²⁺ entry is a consequence of abnormal Septin filament architecture resulting in aberrant ER-PM contacts. The importance of membrane contacts for maintaining precise cellular signaling has been recognized previously. However, the molecular mechanism by which Septin filaments organize the ER-PM junctions to regulate Ca²⁺ entry through Orai remains to be fully understood.