Gq protein-coupled receptors as targets for anesthetics

The mechanisms of action of anesthetics are unclear. Much attention has been focused on ion channels in the central nervous system as targets for anesthetics. During the last decade, major advances have been made in our understanding of the physiology and pharmacology of G-protein-coupled receptor (GPCR) signaling. Several lines of studies have shown that GPCRs are targets for anesthetics and that some anesthetics inhibit the functions of Gq-coupled receptors, including muscarinic acetylcholine (ACh) M(1), metabotropic type 5 glutamate, 5-hydroxytryptamine (5-HT) type 2A, and substance P receptors. Nearly 160 GPCRs have been identified, based on their gene sequence and ability to interact with known endogenous ligands. However, an estimated 500-800 additional GPCRs have been classified as "orphan" receptors (oGPCRs) because their endogenous ligands have not yet been identified. Given that known GPCRs are targets for anesthetics, these oGPCRs represent a rich group of receptor targets for anesthetics. This article highlights the effects of anesthetics on Gq-coupled receptors, and discusses whether GPCRs other than Gq-coupled receptors are targets for anesthetics.     

Yin and Yang of ginseng pharmacology： ginsenosides vs gintonin

Ginseng, the root of Panaxginseng, has been used in traditional Chinese medicine as a tonic herb that provides many beneficial effects. Pharmacologic studies in the last decades have shown that ginsenosides （ginseng saponins） are primarily responsible for the actions of ginseng. However, the effects of ginseng are not fully explained by ginsenosides. Recently, another class of active ingredients called gintonin was identified. Gintonin is a complex of glycosylated ginseng proteins containing lysophosphatidic acids （LPAs） that are the intracellular lipid mitogenic mediator. Gintonin specifically and potently activates the G protein-coupled receptors （GPCRs） for LPA. Thus, the actions of ginseng are now also linked to LPA and its GPCRs. This linkage opens new dimensions for ginseng pharmacology and LPA therapeutics. In the present review, we evaluate the pharmacology of ginseng with the traditional viewpoint of Yin and Yang components. Furthermore, we will compare ginsenoside and gintonin based on the modern view of molecular pharmacology in terms of ion channels and GPCRs.     

Emerging molecular mechanisms of general anesthetic action

General anesthetics are essential to modern medicine, and yet a detailed understanding of their mechanisms of action is lacking. General anesthetics were once believed to be "drugs without receptors" but this view has been largely abandoned. During the past decade significant progress in our understanding of the mechanisms of general anesthetic action at the molecular, cellular and neural systems levels has been made. Different molecular targets in various regions of the nervous system are involved in the multiple components of anesthetic action, and these targets can vary between specific anesthetics. Neurotransmitter-gated ion channels, particularly receptors for GABA and glutamate, are modulated by most anesthetics, at both synaptic and extrasynaptic sites, and additional ion channels and receptors are also being recognized as important targets for general anesthetics. In this article, these developments, which have important implications for the development of more-selective anesthetics, are reviewed in the context of recent advances in ion channel structure and function.     

The influence of target family and functional activity on the physicochemical properties of pre-clinical compounds

The target families of greatest interest in drug discovery can be differentiated on the basis of the physicochemical properties of their pre-clinical ligands. The ligands for peptidergic targets, such as peptide GPCRs and integrin receptors, possess significantly higher median property values than those for aminergic targets, such as monoamine transporters and GPCRs. The ligands for peptide GPCRs were found to be less efficient, in terms of their binding energy per unit of molecular weight or lipophilicity, than ligands for monoamine GPCRs. The changes in the property values during the optimization process were found to vary only slightly across the target families, with the main determinant of the drug-likeness of the optimized compounds being the profile of the starting compounds. Agonists for monoamine GPCRs, opioid receptors and ion channels were typically smaller and less lipophilic than the antagonists, but there was no difference between the agonists and the antagonists for peptide GPCRs and nuclear receptors.     

The Effects of General Anesthetics on Synaptic Transmission

General anesthetics are a class of drugs that target the central nervous system and are widely used for various medical procedures. General anesthetics produce many behavioral changes required for clinical intervention, including amnesia, hypnosis, analgesia, and immobility; while they may also induce side effects like respiration and cardiovascular depressions. Understanding the mechanism of general anesthesia is essential for the development of selective general anesthetics which can preserve wanted pharmacological actions and exclude the side effects and underlying neural toxicities. However, the exact mechanism of how general anesthetics work is still elusive. Various molecular targets have been identified as specific targets for general anesthetics. Among these molecular targets, ion channels are the most principal category, including ligand-gated ionotropic receptors like γ-aminobutyric acid, glutamate and acetylcholine receptors, voltage-gated ion channels like voltage-gated sodium channel, calcium channel and potassium channels, and some second massager coupled channels. For neural functions of the central nervous system, synaptic transmission is the main procedure for which information is transmitted between neurons through brain regions, and intact synaptic function is fundamentally important for almost all the nervous functions, including consciousness, memory, and cognition. Therefore, it is important to understand the effects of general anesthetics on synaptic transmission via modulations of specific ion channels and relevant molecular targets, which can lead to the development of safer general anesthetics with selective actions. The present review will summarize the effects of various general anesthetics on synaptic transmissions and plasticity.     

Resolution of controversies in drug/receptor interactions by protein structure. Limitations and pharmacological solutions

Structural biology offers breakthroughs for key issues in receptors, ion channels and transporters. Unfortunately, while knowledge is growing exponentially about receptors and drug targets, there is also an exponential knowledge of all the variables involved. A key issue for structure-based drug design is if there are distinct outcomes from a single structurally defined site. The ways in which drugs can interact with G-protein-coupled receptors (GPCRs) at the orthosteric site can be multiple, and ligands can also interact with allosteric sites. Receptors may exist as homo- or heterodimers, with the potential for distinct pharmacology, and NC-IUPHAR has proposed stringent criteria for recognition of heterodimers (Pin et al., 2007). Furthermore, some drugs have the capacity for activating different signalling cascades from a single receptor (Urban et al., 2007) indicating unique pharmacology. Thus although specific drugs were the main tool by which receptors were (and still can be, if appropriate precautions are taken) classified, drugs may also have distinct pharmacology at certain receptors depending on their chemical structure, showing drug-specific pharmacology rather than the specific-drug pharmacology which had been used in the past to define (and limit) drug classes. Primary structure is an essential but occasionally treacherous tool for defining receptors because distinct primary structures may evolve to perform similar function. This has immense implications in drug screening, and development - which also entails much testing, and selection, in pathophysiological situations.     

N-Acyl amino acids and N-acyl neurotransmitter conjugates: neuromodulators and probes for new drug targets

The myriad functions of lipids as signalling molecules is one of the most interesting fields in contemporary pharmacology, with a host of compounds recognized as mediators of communication within and between cells. The N-acyl conjugates of amino acids and neurotransmitters (NAANs) have recently come to prominence because of their potential roles in the nervous system, vasculature and the immune system. NAAN are compounds such as glycine, GABA or dopamine conjugated with long chain fatty acids. More than 70 endogenous NAAN have been reported although their physiological role remains uncertain, with various NAAN interacting with a low affinity at G protein coupled receptors (GPCR) and ion channels. Regardless of their potential physiological function, NAAN are of great interest to pharmacologists because of their potential as flexible tools to probe new sites on GPCRs, transporters and ion channels. NAANs are amphipathic molecules, with a wide variety of potential fatty acid and headgroup moieties, a combination which provides a rich source of potential ligands engaging novel binding sites and mechanisms for modulation of membrane proteins such as GPCRs, ion channels and transporters. The unique actions of subsets of NAAN on voltage-gated calcium channels and glycine transporters indicate that the wide variety of NAAN may provide a readily exploitable resource for defining new pharmacological targets. Investigation of the physiological roles and pharmacological potential of these simple lipid conjugates is in its infancy, and we believe that there is much to be learnt from their careful study.     

Inhaled drugs of abuse enhance serotonin-3 receptor function

Despite the prevalence of their use, little is currently known of the molecular mechanisms of action of inhaled drugs of abuse. Recent studies have shown effects on NMDA, GABA(A) and glycine receptors in vitro, suggesting that inhalants may exert at least some of their pharmacological effects on ligand-gated ion channels. Enhancement of serotonin-3 receptor function has been shown to play a role in the reinforcing properties of drugs of abuse. We tested the hypothesis that the commonly abused inhaled agents 1,1,1-trichloroethane, trichloroethylene, and toluene enhance serotonin-3 receptor function. All three inhalants significantly and reversibly potentiated, in a dose-dependent manner, serotonin-activated currents mediated by mouse serotonin-3A receptors expressed in Xenopus oocytes. Our findings add the serotonin-3 receptor to the growing list of molecular targets commonly affected by both inhalants and classic CNS depressants such as ethanol and the volatile anesthetics.     

Heterodimerization of g protein-coupled receptors: specificity and functional significance

G protein-coupled receptors (GPCRs) are cell surface receptors that mediate physiological responses to a diverse array of stimuli. GPCRs have traditionally been thought to act as monomers, but recent evidence suggests that GPCRs may form dimers (or higher-order oligomers) as part of their normal trafficking and function. In fact, certain GPCRs seem to have a strict requirement for heterodimerization to attain proper surface expression and functional activity. Even those GPCRs that do not absolutely require heterodimerization may still specifically associate with other GPCR subtypes, sometimes resulting in dramatic effects on receptor pharmacology, signaling, and/or internalization. Understanding the specificity and functional significance of GPCR heterodimerization is of tremendous clinical importance since GPCRs are the molecular targets for numerous therapeutic drugs.     

芋螺镇痛多肽研究进展

芋螺多肽由芋螺毒液管和毒囊内壁的毒腺所分泌,大多数芋螺多肽由10～40个氨基酸残基组成,且富含二硫键,能特异性作用于乙酰胆碱受体 (nAChR),及钙、钠、钾等多种离子通道亚型。目前已发现作用于N-型钙通道、nAChR的α9α10亚基、TTX-R钠通道、NMDA受体的芋螺多肽具有很强的镇痛活性,其中N-型钙通道抑制剂ω-MVIIA已于2004年上市。该类镇痛多肽具有相对分子质量小、结构稳定、活性及选择性高等特点。芋螺镇痛多肽不仅会成为镇痛机制等相关神经生物学研究的重要工具,也会为开发新一代无致瘾镇痛药起到重要作用。本文对芋螺镇痛多肽研究的最新进展予以评述,着重介绍芋螺镇痛多肽的作用靶位、构效关系及其应用进展。     

Sigma-1 receptors and animal studies centered on pain and analgesia

Introduction: Neuropathic pain is difficult to relieve with standard analgesics and tends to be resistant to opioid therapy. Sigma-1 receptors activated during neuropathic injury may sustain pain. Neuropathic injury activates sigma-1 receptors, which results in activation of various kinases, modulates the activity of multiple ion channels, ligand activated ion channels and voltage-gated ion channels; alters monoamine neurotransmission and dampens opioid receptors G-protein activation. Activation of sigma-1 receptors tonically inhibits opioid receptor G-protein activation and thus dampens analgesic responses. Therefore, sigma-1 receptor antagonists are potential analgesics for neuropathic and adjuvants to opioid therapy.

Areas covered: This article reviews the importance of sigma-1 receptors as pain generators in multiple animal models in order to illustrate both the importance of these unique receptors in pathologic pain and the potential benefits to sigma-1 receptor antagonists as analgesics.

Expert opinion: Sigma-1 receptor antagonists have a great potential as analgesics for acute neuropathic injury (herpes zoster, acute postoperative pain and chemotherapy induced neuropathy) and may, as an additional benefit, prevent the development of chronic neuropathic pain. Antagonists are potentially effective as adjuvants to opioid therapy when used early to prevent analgesic tolerance. Drug development is complicated by the complexity of sigma-1 receptor pharmacodynamics and its multiple targets, the lack of a specific sigma-1 receptor antagonist, and potential side effects due to on-target toxicities (cognitive impairment, depression).     

Pharmacogenetics of new analgesics

Patient phenotypes in pharmacological pain treatment varies between individuals, which could be partly assigned to their genotypes regarding the targets of classical analgesics (OPRM1, PTGS2) or associated signalling pathways (KCNJ6). Translational and genetic research have identified new targets, for which new analgesics are being developed. This addresses voltage-gated sodium, calcium and potassium channels, for which SCN9A, CACNA1B, KCNQ2 and KCNQ3, respectively, are primary gene candidates because they code for the subunits of the respective channels targeted by analgesics currently in clinical development. Mutations in voltage gated transient receptor potential (TRPV) channels are known from genetic pain research and may modulate the effects of analgesics under development targeting TRPV1 or TRPV3. To this add ligand-gated ion channels including nicotinic acetylcholine receptors, ionotropic glutamate-gated receptors and ATP-gated purinergic P2X receptors with most important subunits coded by CHRNA4, GRIN2B and P2RX7. Among G protein coupled receptors, δ-opioid receptors (coded by OPRD1), cannabinoid receptors (CNR1 and CNR2), metabotropic glutamate receptors (mGluR5 coded by GRM5), bradykinin B(1) (BDKRB1) and 5-HT(1A) (HTR1A) receptors are targeted by new analgesic substances. Finally, nerve growth factor (NGFB), its tyrosine kinase receptor (NTRK1) and the fatty acid amide hydrolase (FAAH) have become targets of interest. For most of these genes, functional variants have been associated with neuro-psychiatric disorders and not yet with analgesia. However, research on the genetic modulation of pain has already identified variants in these genes, relative to pain, which may facilitate the pharmacogenetic assessments of new analgesics. The increased number of candidate pharmacogenetic modulators of analgesic actions may open opportunities for the broader clinical implementation of genotyping information.     

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂

There are at least two types of cannabinoid receptors (CB(1) and CB(2)). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ(9)-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB(1), non-CB(2) established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB(1) and/or CB(2) receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel "CB(3)" cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB(1), non-CB(2) pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB(3) receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB(1) receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB(1)/CB(2) receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB(1), non-CB(2) cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.     

Putative Roles of Astrocytes in General Anesthesia

General anesthetics are a mainstay of modern medicine, and although much progress has been made towards identifying molecular targets of anesthetics and neural networks contributing to endpoints of general anesthesia, our understanding of how anesthetics work remains unclear. Reducing this knowledge gap is of fundamental importance to prevent unwanted and life-threatening side-effects associated with general anesthesia. General anesthetics are chemically diverse, yet they all have similar behavioral endpoints, and so for decades, research has sought to identify a single underlying mechanism to explain how anesthetics work. However, this effort has given way to the ‘multiple target hypothesis’ as it has become clear that anesthetics target many cellular proteins, including GABA_A receptors, glutamate receptors, voltage-independent K⁺ channels, and voltage-dependent K⁺, Ca²⁺ and Na⁺ channels, to name a few. Yet, despite evidence that astrocytes are capable of modulating multiple aspects of neural function and express many anesthetic target proteins, they have been largely ignored as potential targets of anesthesia. The purpose of this brief review is to highlight the effects of anesthetic on astrocyte processes and identify potential roles of astrocytes in behavioral endpoints of anesthesia (hypnosis, amnesia, analgesia, and immobilization).     

Opportunities for functional selectivity in GPCR antibodies

Monoclonal antibodies (mAbs) have been used for decades as tools to probe the biology and pharmacology of receptors in cells and tissues. They are also increasingly being developed for clinical purposes against a broad range of targets, albeit to a lesser extent for G-protein-coupled receptors (GPCRs) relative to other therapeutic targets. Recent pharmacological, structural and biophysical data have provided a great deal of new insight into the molecular details, complexity and regulation of GPCR function. Whereas GPCRs used to be viewed as having either “on” or “off” conformational states, it is now recognized that their structures may be finely tuned by ligands and other interacting proteins, leading to the selective activation of specific signaling pathways. This information coupled with new technologies for the selection of mAbs targeting GPCRs will be increasingly deployed for the development of highly selective mAbs that recognize conformational determinants leading to novel therapeutics.     

Inhibitory ligand-gated ion channels as substrates for general anesthetic actions

General anesthetics have been in clinical use for more than 160 years. Nevertheless, their mechanism of action is still only poorly understood. In this review, we describe studies suggesting that inhibitory ligand-gated ion channels are potential targets for general anesthetics in vitro and describe how the involvement of y-aminobutyric acid (GABA)(A) receptor subtypes in anesthetic actions could be demonstrated by genetic studies in vivo.     

Structure-based drug screening for G-protein-coupled receptors

G-protein-coupled receptors (GPCRs) represent a large family of signaling proteins that includes many therapeutic targets; however, progress in identifying new small molecule drugs has been disappointing. The past 4 years have seen remarkable progress in the structural biology of GPCRs, raising the possibility of applying structure-based approaches to GPCR drug discovery efforts. Of the various structure-based approaches that have been applied to soluble protein targets, such as proteases and kinases, in silico docking is among the most ready applicable to GPCRs. Early studies suggest that GPCR binding pockets are well suited to docking, and docking screens have identified potent and novel compounds for these targets. This review will focus on the current state of in silico docking for GPCRs.     

全麻效应的受体机制

随着配体门控型离子通道分子克隆研究技术的发展,对由特定亚单位组成的重组受体的药理学研究成为可能。近年来,许多实验室应用此技术对产生全麻效应的麻醉药的作用机制进行了研究。大多数吸入性和静脉麻醉药对GABA_A受体有不同程度的增强调制作用。甘氨酸,AMPA,红藻氨酸,NMDA以及5-HT_3受体等也都是许多麻醉药的作用靶。某些全麻药对受体作用的亚单位特异性提示,通过构建和研究嵌合受体可能最终会找出决定全麻效应的特定氨基酸序列。     

Novel cannabinoid receptors

Cannabinoids have numerous physiological effects. In the years since the molecular identification of the G protein-coupled receptors CB1 and CB2, the ion channel TRPV1, and their corresponding endogenous ligand systems, many cannabinoid-evoked actions have been shown conclusively to be mediated by one of these specific receptor targets. However, there remain several examples where these classical cannabinoid receptors do not explain observed pharmacology. Studies using mice genetically deleted for the known receptors have confirmed the existence of additional targets, which have come to be known collectively as non-CB1/CB2 receptors. Despite intense research efforts, the molecular identity of these non-CB1/CB2 receptors remains for the most part unclear. Two orphan G protein-coupled receptors have recently been implicated as novel cannabinoid receptors; these are GPR119, which has been proposed as a receptor for oleoylethanolamide, and GPR55 which has been proposed as a receptor activated by multiple different cannabinoid ligands. In this review I will present an introduction to non-CB1/CB2 pharmacology, summarize information on GPR55 and GPR119 currently available, and consider their phylogenetic origin and what aspects of non-CB1/CB2 pharmacology, if any, they help explain.