Cold Spring Harbor perspectives in biology最新文献

Inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃Rs) are ubiquitously expressed intracellular calcium (Ca²⁺) release channels predominantly localized to the endoplasmic reticulum. There are three IP₃R subtypes, which assemble as homo-/heterotetramers. The opening of IP₃Rs requires binding of one IP₃ per monomer and Ca²⁺ Recent high-resolution cryogenic electron microscopy (cryo-EM) structures of IP₃Rs in combination with functional assays have greatly increased our understanding of the structural basis for IP₃R channel opening and closing. IP₃R channel activation is facilitated by IP₃ and Ca²⁺ binding to the activation site. Channel inactivation occurs in the presence of IP₃ and high Ca²⁺ when Ca²⁺ is bound to the low-affinity Ca²⁺-binding motif. Specifically, in the near atomic resolution structures of IP₃Rs, densities corresponding to the primary agonists-IP₃ and Ca²⁺-and the allosteric modulator adenosine triphosphate (ATP) were identified. In this article, we aim to provide a comprehensive overview of the current understanding of structure-function relationships for IP₃Rs mediated by IP₃, Ca²⁺, and ATP.

Calcium ions (Ca²⁺) are essential second messengers intimately implicated in a variety of biological processes, ranging from short-term events such as muscle contraction to long-term effects like gene expression. Dysregulated Ca²⁺ signaling can disrupt cellular function and contribute to the development of various human diseases, including developmental, neurological, immunoinflammatory, metabolic, and cardiovascular disorders. To study the mechanisms and biological consequences of Ca²⁺ signaling, optogenetic approaches have proven invaluable, as they offer exceptional spatiotemporal resolution compared to traditional methods. Recent progress in non-opsin-based optogenetics, particularly those engineered from Ca²⁺ release-activated Ca²⁺ (CRAC) channels, has substantially advanced our understanding of Ca²⁺ signaling mechanisms. These tools have enabled precise manipulation of downstream signaling events, opening new avenues for therapeutic interventions. In this review, we examine the principles behind the design and engineering of light-sensitive calcium actuators and modulators (designated LiCAMs) and the applications of representative LiCAMs in remote and noninvasive control of Ca²⁺-modulated physiological processes both in vitro and in vivo.

The collection of articles on the theme Evolution and Development of Neural Circuits explores how brains are built, diversified, and adapted in a variety of species, integrating perspectives from evolutionary biology, developmental neuroscience, and systems neurobiology. Recent advances in molecular genetics, neuroanatomy, physiology, imaging, and computational modeling have enabled unprecedented insights into the mechanisms that shape neural circuits. This collection brings together contributions from leading investigators who examine the architecture and function of neural circuits from multiple angles. Key themes include the evolutionary divergence and convergence of circuit motifs, the conserved molecular and developmental building blocks that underlie connectivity, and the selective pressures that sculpt neural systems to support behavior and cognition. Articles cover topics ranging from retinal mapping and interneuron diversity to thalamocortical connectivity, prefrontal circuit maturation, and the computational modeling of both normal and abnormal circuit development. Collectively, these essays reveal how molecular signaling, cellular variability, and theoretical principles converge to shape the formation and function of circuits across vertebrate and invertebrate brains.

Chandelier cells (ChCs) represent a unique GABAergic interneuron in the cortex, yet our knowledge of this sparsely populated cell type has remained equally sparse for many years. New tools, however, have brought ChCs out of the shadows, shedding light on their development and function in the rodent brain and, gradually, gaining insights into their properties in primates. This review will focus on the developmental mechanisms that define ChCs as a unique cell type and, where possible, draw parallels to studies in primates, particularly to work in human tissue. What emerges is a picture of a highly plastic neuron with a unique developmental trajectory that appears to be genetically and functionally conserved in the primate brain.

Intracellular calcium (Ca²⁺) signaling is shaped by the coordinated action of pumps, channels, transporters, and Ca²⁺-binding proteins including the cytosolic annexins, which decode changes in cellular Ca²⁺ levels and are crucial components of this intricate system. Here, we dissect overarching themes in annexin biology, detailing their structure, functional capabilities, and roles within the cellular context. We describe their bimodular structure consisting of the core domain with the Ca²⁺- and membrane-binding sites that classify the proteins and the amino-terminal domain containing sites for proteolytic cleavage, phosphorylation, and protein interaction including complex formation with S100 family Ca²⁺-binding proteins. We examine their Ca²⁺ sensing and lipid/membrane binding properties and discuss experimental evidence toward their functions in building Ca²⁺-controlled platforms for dynamic assembly of functional machineries at specific membrane domains within the complex regulatory networks of cellular function.

Ribosomal frameshifting is a recoding mechanism that allows the ribosome to alter its reading frame during translation, often in response to specific messenger RNA (mRNA) elements or cellular conditions. While essential for the life cycle of many viruses, frameshifting also occurs spontaneously or in response to transfer RNA (tRNA) depletion, raising important questions about its regulation and biological relevance. This review explores the structural and kinetic principles that govern -1 frameshifting, highlighting the role of ribosome conformational dynamics, slippery sequences, and mRNA secondary structures. We discuss how programmed, hungry, and spontaneous frameshifting arise from distinct molecular pathways, yet converge on shared mechanistic features. The review also examines translational bypassing as a related form of recoding that involves large-scale ribosome sliding over noncoding regions and relies on a distinct set of RNA and ribosome conformational cues to ensure accurate take-off and landing. These insights expand our understanding of translation fidelity and recoding plasticity.

Electric field-guided cell migration, known as galvanotaxis or electrotaxis, has garnered great interest as an engineering manipulation but has not been widely considered physiologically relevant. Here we provide experimental evidence proving galvanotaxis is a fundamental biological process, like chemotaxis, and show that the application of electric fields provides a powerful engineering approach. We will review our understanding of (1) endogenous electric fields naturally found in biological systems; (2) galvanotaxis of different cell types; and (3) sensing and signaling mechanisms of galvanotaxis. We reason that the bioelectrical mechanism is likely to be part of the environmental cues that cells and tissues integrate to make motility decisions.

Telomerase emerged in early eukaryotes as a highly specialized reverse transcriptase for maintaining chromosome integrity. The telomerase enzyme contains an integral RNA, providing the template for DNA repeat synthesis. This central telomerase RNA not only provides the template but also contributes to the enzyme's catalytic function and the biogenesis of the ribonucleoprotein. Remarkably, telomerase RNA exhibits significant diversity in sequence, structure, and biogenesis across eukaryotic lineages, a feature that sets it apart from other functional RNAs. In ciliates and plants, telomerase RNA is transcribed by RNA polymerase III, whereas in animals and fungi, it is predominantly transcribed by RNA polymerase II. These differences result in distinct pathways for RNA synthesis, maturation, and trafficking. This work highlights how the diversity in size and structure of telomerase RNAs impacts the complexity and evolution of telomerase ribonucleoproteins, spanning from unicellular eukaryotes to multicellular plants and animals, highlighting telomerase RNA's critical role in telomere biology.

One of the prime examples of the applicability of Mendel's laws to the animal world involves the characteristics of guinea pig coat color. The paper retraces the history of an especially illustrious example of Mendelian mechanisms in guinea pigs and analyzes its role in the dissemination of genetic theory. Its origins go back to William Castle's cross-breeding experiments conducted in the early 1900s, yet there is a substantial gap between Castle's results in that particular experiment and the canonized form into which they were subsequently molded: a concise chart that simultaneously demonstrates and reaffirms Mendel's laws. The extraordinary appeal of that chart stemmed from scientific, pedagogical, as well as cultural factors, the latter related to the sociopolitical significance of color differences in the context of racial discourse and of concerns about racial mixture. More generally, the guinea pigs chart analyzed here belonged to a family of standardized visualizations that purported to describe empirical findings while actually describing Mendelian theory.

Excitation-contraction coupling (ECC) in skeletal muscle is mediated by mechanical coupling between the L-type voltage-dependent Ca²⁺ channel (Ca_V1.1) in the transverse tubules and the Ca²⁺ release channel (RYR1) in the sarcoplasmic reticulum (SR). However, ECC complexes are much more complicated than just these two ion channels. Triadic Ca²⁺ release units (CRUs) that mediate ECC in skeletal muscle are allosterically regulated complexes of ion channels, cytoplasmic modulators, SR transmembrane proteins, and lumenal Ca²⁺ buffers. While RYR1, Ca_V1.1α_1s, and Ca_V1.1β_1a, the SH3 and cysteine-rich domain protein (STAC3) and junctophilin (JPH1 and/or JPH2) are required for voltage-gated Ca²⁺ release, other auxiliary proteins modulate this process. In this review, we discuss what is known about the proteins in the triadic protein complex, their roles in ECC, and the mutations in the ECC proteins that give rise to skeletal muscle myopathies.