Molecules and Cells最新文献

Bidirectional trans-synaptic signaling directs synapse formation and neural circuit assembly. Increasing evidence supports that several subfamilies of adhesion G protein-coupled receptors (aGPCRs) control important mechanistic aspects of synapse assembly and neural circuit wiring by combining trans-synaptic adhesion with GPCR signaling. These subfamilies include Latrophilins (ADGRL), CELSRs (cadherin EGF LAG seven-transmembrane receptors/ADGRC), and BAIs (brain angiogenesis inhibitors/ADGRB). Recently, aGPCRs have been linked to neurological disorders, further emphasizing the important roles of these receptors for proper neurological functions. Here, we discuss our current understanding of the functions of several aGPCRs in synaptic circuits and their links to neurological and neurodevelopmental disorders.

The voltage-gated channel subfamily Q member 4 (KCNQ4), a K+ channel, is one of the most frequently mutated genes in autosomal dominant non-syndromic hearing loss. KCNQ4, which contains six transmembrane domains and a long cytoplasmic C-terminal tail, plays a crucial role in K+ recycling in the inner ear. Although KCNQ4 binds to various interactors, specific binding sites of the interactors remain elusive, and the biological significance of these interactions remains unknown. Therefore, this study aimed to discover a novel interactor of KCNQ4 and delineate its functional role in KCNQ4 regulation. We discovered a novel interactor of KCNQ4, huntingtin-associated protein 1 (HAP1), in addition to calmodulin, which interacts with the C-terminus of KCNQ4 using a yeast two-hybrid assay. This interaction requires the B-segment of KCNQ4 as demonstrated by protein domain analysis. A thorough investigation of the biochemical and physiological consequences of this association revealed that HAP1 overexpression reduced surface expression and attenuated the potassium current mediated by KCNQ4. This suggests that HAP1 acts as a negative regulator of KCNQ4, potentially through the disruption of normal endocytic trafficking. These findings enhance the understanding of KCNQ4 regulation at the molecular level and highlight the potential of the HAP1-KCNQ4 axis as a target for interventions aimed at maintaining channel surface stability.

For over a decade, synaptic cell-adhesion molecules (CAMs) have been recognized as fundamental determinants of neural circuit specificity and diversity. Among the CAMs, leucine-rich repeat (LRR)-containing transmembrane proteins have been established as crucial regulators of synaptic properties across diverse cell-types and brain regions. This minireview focuses on two families of LRR-containing CAMs: leucine-rich repeat transmembrane proteins (LRRTMs) and the Slit and Trk-like family (Slitrks). We provide a comprehensive synthesis of significant findings on LRRTMs and Slitrks since their initial characterization more than 15 years ago. Furthermore, we outline key unresolved questions to stimulate future studies on their functional mechanisms in neural circuit assembly and their pathophysiological roles in various neurological disorders.

Bacterial pathogens have evolved sophisticated strategies to manipulate host cellular processes, ensuring survival, replication, and long-term persistence. Beyond classical immune signaling, emerging evidence highlights the central role of epigenetic regulation in host-pathogen interactions. Pathogens exploit host chromatin through two principal mechanisms: (1) direct modification of histones by bacterial effector proteins with intrinsic enzymatic activities and (2) indirect modulation of host epigenetic states through alterations in signaling pathways or cellular metabolism. These interventions alter post-translational histone modifications-acetylation, methylation, phosphorylation, and lactylation-thereby reshaping transcriptional programs to suppress antimicrobial responses, promote immune tolerance, or establish persistent infection. This review summarizes recent advances in understanding the dynamic interplay between bacterial virulence and host chromatin regulation, highlighting epigenetic reprogramming as a key determinant of infection outcomes.

Stress-related psychiatric disorders are underpinned by dysfunction in the prefrontal cortex and hippocampus; however, the underlying circuit-specific mechanisms remain ill-defined. Here, we identified the basolateral amygdala (BLA)-to-ventral hippocampus (vHPC) circuit as a critical regulator of stress-coping behaviors. Although chronic social defeat stress reduced the mGluR5 expression in both the vHPC and medial prefrontal cortex (mPFC), our circuit-specific behavioral analysis revealed that the activation of the BLA-vHPC circuit produced a significantly greater improvement in coping behavior compared with the activation of the BLA-mPFC circuit. Subsequently, we mechanistically demonstrated that reduced mGluR5 in the vHPC directly impairs CREB-mediated brain-derived neurotrophic factor (BDNF) transcription, a molecular cascade tightly linked to passive coping. These findings reveal a novel circuit-specific molecular mechanism governing stress recovery, positioning the mGluR5-BDNF pathway as a highly specific and promising therapeutic target for future gene therapy interventions.

The synaptic nanocluster refers to the nanoscale accumulation of synaptic proteins that ensures the fidelity of synaptic transmission. These nanoclusters align pre- and post-synaptic machineries across the synaptic cleft, enabling neurotransmitter release to occur precisely opposite postsynaptic receptors. In vertebrates, neuroligins are key postsynaptic cell adhesion molecules that help maintain synaptic function. Recent superresolution microscopy studies have shown that neuroligins themselves form nanoclusters and regulate the nanoscale distribution of synaptic proteins, suggesting a role in orchestrating synaptic strength through nanocluster organization. In this review, we summarize recent advances in understanding how neuroligin subtype specificity influences the organization of postsynaptic receptors and how neuroligin-ligand interactions modulate nanoscale architecture. We also discuss how disruption in those nanoclusters can disturb synaptic strength.

Open chromatin profiling identifies regulatory DNA regions that are accessible to transcription factors and other proteins, offering insights into gene regulation. Although ATAC-seq is commonly used for mapping open chromatin, standard techniques such as DNase-seq and ATAC-seq have limitations, including the need for large cell numbers or fresh (unfixed) samples. NicE-seq offers an alternative approach by using nicking endonucleases combined with polymerase-mediated biotin labeling. Here, we present a detailed analysis framework for NicE-seq data in plants using Arabidopsis thaliana as our reference species, adapted from the nf-core/atacseq pipeline with specific modifications. We emphasize the analytical differences between NicE-seq and ATAC-seq, describe data processing workflows, and illustrate methods for peak calling, annotation, and integration with transcriptomic data. This computational resource aims to guide researchers in applying NicE-seq, providing a basis for selecting between NicE-seq and ATAC-seq in plant epigenomic research, especially when working with challenging samples such as archived tissues or small cell populations.