Effects of Conus peptides on the behavior of mice

When different cone snail peptides are injected into the CNS of vertebrates, they elicit diverse behaviors primarily because of their selectivity for specific receptor or ion channel subtypes. The subcellular context of the highly localized targets (i.e. the presence of other cellular elements that are functionally linked to the targets of conopeptides) is another determinant of the elicited behavior. Recent studies have advanced our understanding of the mechanisms by which four conopeptides produce different behaviors in mice.     

Molecular Phylogeny, Classification and Evolution of Conopeptides

Conopeptides are toxins expressed in the venom duct of cone snails (Conoidea, Conus). These are mostly well-structured peptides and mini-proteins with high potency and selectivity for a broad range of cellular targets. In view of these properties, they are widely used as pharmacological tools and many are candidates for innovative drugs. The conopeptides are primarily classified into superfamilies according to their peptide signal sequence, a classification that is thought to reflect the evolution of the multigenic system. However, this hypothesis has never been thoroughly tested. Here we present a phylogenetic analysis of 1,364 conopeptide signal sequences extracted from GenBank. The results validate the current conopeptide superfamily classification, but also reveal several important new features. The so-called "cysteine-poor" conopeptides are revealed to be closely related to "cysteine-rich" conopeptides; with some of them sharing very similar signal sequences, suggesting that a distinction based on cysteine content and configuration is not phylogenetically relevant and does not reflect the evolutionary history of conopeptides. A given cysteine pattern or pharmacological activity can be found across different superfamilies. Furthermore, a few conopeptides from GenBank do not cluster in any of the known superfamilies, and could represent yet-undefined superfamilies. A clear phylogenetically based classification should help to disentangle the diversity of conopeptides, and could also serve as a rationale to understand the evolution of the toxins in the numerous other species of conoideans and venomous animals at large.     

Toxins from cone snails: properties,applications and biotechnological production

Cone snails are marine predators that use venoms to immobilize their prey. The venoms of these mollusks contain a cocktail of peptides that mainly target different voltage- and ligand-gated ion channels. Typically, conopeptides consist of ten to 30 amino acids but conopeptides with more than 60 amino acids have also been described. Due to their extraordinary pharmacological properties, conopeptides gained increasing interest in recent years. There are several conopeptides used in clinical trials and one peptide has received approval for the treatment of pain. Accordingly, there is an increasing need for the production of these peptides. So far, most individual conopeptides are synthesized using solid phase peptide synthesis. Here, we describe that at least some of these peptides can be obtained using prokaryotic or eukaryotic expression systems. This opens the possibility for biotechnological production of also larger amounts of long chain conopeptides for the use of these peptides in research and medical applications.     

Neurobiology of sexual behavior

Recent advances in the neurobiology of sexual behavior have helped to refine our understanding of the neuroanatomical, neuroendocrine and neurochemical systems that modulate responses to sexual stimulation. Both appetitive and consummatory sexual behaviors have been studied in several laboratory species and in humans using traditional and novel behavioral paradigms. New knowledge has emerged concerning the role of hypothalamic, limbic and brainstem structures, neuropeptides, brain monoamines and nitric oxide in the control of partner preference, sexual desire, erection, copulation, ejaculation, orgasm and sexual satiety. Brain imaging of visually evoked sexual arousal in humans has also been examined.     

Signal acquisition and analysis for cortical control of neuroprosthetics

Work in cortically controlled neuroprosthetic systems has concentrated on decoding natural behaviors from neural activity, with the idea that if the behavior could be fully decoded it could be duplicated using an artificial system. Initial estimates from this approach suggested that a high-fidelity signal comprised of many hundreds of neurons would be required to control a neuroprosthetic system successfully. However, recent studies are showing hints that these systems can be controlled effectively using only a few tens of neurons. Attempting to decode the pre-existing relationship between neural activity and natural behavior is not nearly as important as choosing a decoding scheme that can be more readily deployed and trained to generate the desired actions of the artificial system. These artificial systems need not resemble or behave similarly to any natural biological system. Effective matching of discrete and continuous neural command signals to appropriately configured device functions will enable effective control of both natural and abstract artificial systems using compatible thought processes.     

Will combinatorial chemistry deliver real medicines?

Over the next decade, the impact of library synthesis will play a major role in shortening the lead optimization phase of drug discovery. The prognosis for combinatorial chemistry to discover fundamentally different new classes of therapeutically active small molecules against some of the more difficult biological targets is less certain. Expectations are high because the technology potentially allows us to sample available drug space by synthesizing all possible small molecule ligands (variously estimated to be between 10³⁰–10⁵⁰ compounds). Some caution is advised, however, since, despite recent increases in high-throughput screening of substantially greater numbers of synthetic compounds and natural products, we are not routinely finding a plethora of new structures. The outcome may be that combinatorial chemistry offers us the ability to work faster on finding ligands for well-established tractable targets, such as G-protein-coupled receptors, ion channels or proteases, rather than, say, the more complex protein—protein interactions which from the majority of targets in signal transduction pathways.     

Pacemaker neurons and neuronal networks: an integrative view

Rhythmically active neuronal networks give rise to rhythmic motor activities but also to seemingly non-rhythmic behaviors such as sleep, arousal, addiction, memory and cognition. Many of these networks contain pacemaker neurons. The ability of these neurons to generate bursts of activity intrinsically lies in voltage- and time-dependent ion fluxes resulting from a dynamic interplay among ion channels, second messenger pathways and intracellular Ca2+ concentrations, and is influenced by neuromodulators and synaptic inputs. This complex intrinsic and extrinsic modulation of pacemaker activity exerts a dynamic effect on network activity. The nonlinearity of bursting activity might enable pacemaker neurons to facilitate the onset of excitatory states or to synchronize neuronal ensembles--an interactive process that is intimately regulated by synaptic and modulatory processes.     

Will genetics really revolutionize the drug discovery process?

Genetics has played only a modest role in drug discovery, but new technologies will radically change this. Whole genome sequencing will identify new drug discovery targets, and emerging methods for the determination of gene function will increase the ability to select robust targets. Detection of single nucleotide polymorphisms and common polymorphisms will enhance the investigation of polygenic diseases and the use of genetics in drug development. Oligonucleotide arraying technologies will allow analysis of gene expression patterns in novel ways.     

Proteins

Proteins continue to surprise and amaze us in the myriad of ways in which they achieve biological function. The Proteins section in this issue of Current Opinion in Structural Biology highlights several proteins in which large conformational changes and evolutionary divergence in structure and function, play essential roles in their adaptation to a variety of biological functions. In addition, fundamental advances have been made in research, spurred on by industrial interest in the use of proteins as drug targets or as catalysts. All of the reviews in this section document the fact that multiple crystal structures of a protein in different functional states, and of different members of protein families, are necessary for the composition of a complete structural picture.     

Isolation and Characterization of Conotoxin Protein from Conus inscriptus and Its Potential Anticancer Activity Against Cervical Cancer (HeLa-HPV 16 Associated) Cell Lines

International Journal of Peptide Research and Therapeutics - Marine snails are abundant sources of biologically important conopeptides with their potential applications in drug development. The...     

Isolation,Characterization and In-Silico Study of Conotoxin Protein from Conus loroisii and Its Anti-cancer Activity

International Journal of Peptide Research and Therapeutics - The conopeptides are the conotoxin of Conus loroisii have wide applications in drug development. This work emphasizes the isolation and...     

芋螺毒素氧化折叠研究进展

芋螺毒素(conotoxin,CTX)是当今生物毒素研究的热点之一,已经成为研究药理学和神经科学的重要工具。因此,芋螺毒素如何在体内和体外进行氧化折叠形成天然构象,获得有生物活性的芋螺毒素,越来越为人们所关注。根据当前研究状况,概述了芋螺毒素氧化折叠的一般过程,并总结了二硫键、PDI(二硫键异构酶)、前体肽等在芋螺毒素氧化折叠中所发挥的作用。此外,还就芋螺毒素氧化重折叠的研究前景和方向进行了展望。     

海南产桶形芋螺蛋白质二硫键异构酶的鉴定

蛋白质二硫键异构酶(PDI)是内质网新生肽链折叠中一个重要的折叠酶.在热 带药用海洋生物芋螺的毒液中富含PDI酶,该酶对于毒液中芋螺毒素神经肽的体内 氧化折叠至关重要.本研究主要采用凝胶过滤层析和制备型Rotofor液相等电聚焦 电泳等多种方法,从海南产桶形芋螺（Conus betulinus Linnaeus）毒管中分离 纯化天然的PDI酶蛋白,经电泳和MALDI-TOF MS质谱鉴定分析确证获得了高纯度 的桶形芋螺PDI酶,建立了天然芋螺PDI酶分离纯化的技术方法. 以芋螺毒素线性 肽K412为底物进行了PDI酶活性鉴定.结果表明,该分离纯化的PDI酶能够促进K412 的氧化折叠.由于芋螺毒素的氧化折叠非常复杂,且氧化折叠后具有正确二硫键连 接方式的芋螺毒素才具有各种药理活性,因此,本研究结果为后续PDI酶在种类繁 多的芋螺毒素氧化折叠中的应用及其作用机制研究提供了重要的物质基础.     

Population coding and behavioral choice

Many individual behavioral acts are produced by the combined activity of large populations of broadly tuned neurons, and the neuronal populations for different behaviors can overlap. Recent experiments monitoring and manipulating neuronal activity during behavioral decisions have begun to shed light on the mechanisms that enable overlapping populations of neurons to generate choices between categorically distinct behaviors.     

The spasmodic peptide defines a new conotoxin superfamily

We purified and characterized a peptide from the venom of Conus textile that makes normal mice assume the phenotype of a well-known mutant, the spasmodic mouse. This "spasmodic" peptide has 27 amino acids, including two gamma-carboxyglutamate (Gla) residues. A cDNA clone encoding the precursor for the peptide was identified; a gamma-carboxylation recognition signal sequence (gamma-CRS) is present in the -1 --> -20 region of the peptide precursor. Both the gamma-CRS and the position of the Gla residues in the mature toxin are notably different from other Gla-containing conopeptides. The spasmodic peptide has a novel disulfide framework and distinct signal sequence which together define a new P-superfamily of conopeptides. A cDNA encoding another member of the P-superfamily was identified from a different species, Conus gloriamaris.     

The chemical-biological interface: developments in automated and miniaturised screening technology

The rapidly changing developments in genomics and combinatorial chemistry, generating new drug targets and large numbers of compounds, have caused a revolution in high-throughput screening technologies. Key to this revolution has been the introduction of robotics and automation, together with new biological assay technologies (e.g., homogeneous time resolved fluorescence). With ever increasing workloads, together with economic and logistical constraints, miniaturisation is rapidly becoming essential for the future of high-throughput screening and combinatorial chemistry. This is evident from the introduction of high-density microtitre plates, small volume liquid handling robots and associated detection technology.     

芋螺毒素研究进展

芋螺毒素是近年来国际上的一个研究热点.它属于一类海洋生物活性多肽,多数由12～46个氨基酸残基所组成,能特异性地作用于体内各种离子通道和细胞膜上神经递质和激肽的受体.具有分子质量小、结构多样、作用靶点广泛、功能专一、组织特异性强等优点,因而较之其他生物来源的活性多肽有更多的优越性.芋螺毒素是一待挖掘的“富矿区”,可作为体内一些具有重要生理功能靶点的探针和“解密器”,亦可作为新药的先导化合物或直接开发成新药,因此对芋螺毒素的研究有重要的理论和实际意义.