Showing papers in "Pharmacological Reviews in 2010"

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Abstract: The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2

Abstract: There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ9-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-CB1, non-CB2 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 CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB3” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 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 CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

Abstract: To date, studies suggest that biological signaling by nitric oxide (NO) is primarily mediated by cGMP, which is synthesized by NO-activated guanylyl cyclases and broken down by cyclic nucleotide phosphodiesterases (PDEs). Effects of cGMP occur through three main groups of cellular targets: cGMP-dependent protein kinases (PKGs), cGMP-gated cation channels, and PDEs. cGMP binding activates PKG, which phosphorylates serines and threonines on many cellular proteins, frequently resulting in changes in activity or function, subcellular localization, or regulatory features. The proteins that are so modified by PKG commonly regulate calcium homeostasis, calcium sensitivity of cellular proteins, platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes. Current therapies that have successfully targeted the NO-signaling pathway include nitrovasodilators (nitroglycerin), PDE5 inhibitors [sildenafil (Viagra and Revatio), vardenafil (Levitra), and tadalafil (Cialis and Adcirca)] for treatment of a number of vascular diseases including angina pectoris, erectile dysfunction, and pulmonary hypertension; the PDE3 inhibitors [cilostazol (Pletal) and milrinone (Primacor)] are used for treatment of intermittent claudication and acute heart failure, respectively. Potential for use of these medications in the treatment of other maladies continues to emerge.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

Abstract: Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting β polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) α and β] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases

Abstract: Polymorphonuclear neutrophils are the first cells recruited to inflammatory sites and form the earliest line of defense against invading microorganisms. Neutrophil elastase, proteinase 3, and cathepsin G are three hematopoietic serine proteases stored in large quantities in neutrophil cytoplasmic azurophilic granules. They act in combination with reactive oxygen species to help degrade engulfed microorganisms inside phagolysosomes. These proteases are also externalized in an active form during neutrophil activation at inflammatory sites, thus contributing to the regulation of inflammatory and immune responses. As multifunctional proteases, they also play a regulatory role in noninfectious inflammatory diseases. Mutations in the ELA2/ELANE gene, encoding neutrophil elastase, are the cause of human congenital neutropenia. Neutrophil membrane-bound proteinase 3 serves as an autoantigen in Wegener granulomatosis, a systemic autoimmune vasculitis. All three proteases are affected by mutations of the gene (CTSC) encoding dipeptidyl peptidase I, a protease required for activation of their proform before storage in cytoplasmic granules. Mutations of CTSC cause Papillon-Lefevre syndrome. Because of their roles in host defense and disease, elastase, proteinase 3, and cathepsin G are of interest as potential therapeutic targets. In this review, we describe the physicochemical functions of these proteases, toward a goal of better delineating their role in human diseases and identifying new therapeutic strategies based on the modulation of their bioavailability and activity. We also describe how nonhuman primate experimental models could assist with testing the efficacy of proposed therapeutic strategies.

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

Abstract: The classic view of estrogen actions in the brain was confined to regulation of ovulation and reproductive behavior in the female of all mammalian species studied, including humans. Burgeoning evidence now documents profound effects of estrogens on learning, memory, and mood as well as neurodevelopmental and neurodegenerative processes. Most data derive from studies in females, but there is mounting recognition that estrogens play important roles in the male brain, where they can be generated from circulating testosterone by local aromatase enzymes or synthesized de novo by neurons and glia. Estrogen-based therapy therefore holds considerable promise for brain disorders that affect both men and women. However, as investigations are beginning to consider the role of estrogens in the male brain more carefully, it emerges that they have different, even opposite, effects as well as similar effects in male and female brains. This review focuses on these differences, including sex dimorphisms in the ability of estradiol to influence synaptic plasticity, neurotransmission, neurodegeneration, and cognition, which, we argue, are due in a large part to sex differences in the organization of the underlying circuitry. There are notable sex differences in the incidence and manifestations of virtually all central nervous system disorders, including neurodegenerative disease (Parkinson's and Alzheimer's), drug abuse, anxiety, and depression. Understanding the cellular and molecular basis of sex differences in brain physiology and responses to estrogen and estrogen mimics is, therefore, vitally important for understanding the nature and origins of sex-specific pathological conditions and for designing novel hormone-based therapeutic agents that will have optimal effectiveness in men or women.

Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

Abstract: It is useful to consider seven transmembrane receptors (7TMRs) as disordered proteins able to allosterically respond to a number of binding partners. Considering 7TMRs as allosteric systems, affinity and efficacy can be thought of in terms of energy flow between a modulator, conduit (the receptor protein), and a number of guests. These guests can be other molecules, receptors, membrane-bound proteins, or signaling proteins in the cytosol. These vectorial flows of energy can yield standard canonical guest allostery (allosteric modification of drug effect), effects along the plane of the cell membrane (receptor oligomerization), or effects directed into the cytosol (differential signaling as functional selectivity). This review discusses these apparently diverse pharmacological effects in terms of molecular dynamics and protein ensemble theory, which tends to unify 7TMR behavior toward cells. Special consideration will be given to functional selectivity (biased agonism and biased antagonism) in terms of mechanism of action and potential therapeutic application. The explosion of technology that has enabled observation of diverse 7TMR behavior has also shown how drugs can have multiple (pluridimensional) efficacies and how this can cause paradoxical drug classification and nomenclatures.

International Union of Basic and Clinical Pharmacology. LXXVI. Current Progress in the Mammalian TRP Ion Channel Family

Abstract: Transient receptor potential (TRP) channels are a large family of ion channel proteins, surpassed in number in mammals only by voltage-gated potassium channels. TRP channels are activated and regulated through strikingly diverse mechanisms, making them suitable candidates for cellular sensors. They respond to environmental stimuli such as temperature, pH, osmolarity, pheromones, taste, and plant compounds, and intracellular stimuli such as Ca2+ and phosphatidylinositol signal transduction pathways. However, it is still largely unknown how TRP channels are activated in vivo. Despite the uncertainties, emerging evidence using TRP channel knockout mice indicates that these channels have broad function in physiology. Here we review the recent progress on the physiology, pharmacology and pathophysiological function of mammalian TRP channels.

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

Abstract: The hormone melatonin (5-methoxy- N -acetyltryptamine) is synthesized primarily in the pineal gland and retina, and in several peripheral tissues and organs. In the circulation, the concentration of melatonin follows a circadian rhythm, with high levels at night providing timing cues to target tissues endowed with melatonin receptors. Melatonin receptors receive and translate melatonin's message to influence daily and seasonal rhythms of physiology and behavior. The melatonin message is translated through activation of two G protein-coupled receptors, MT1 and MT2, that are potential therapeutic targets in disorders ranging from insomnia and circadian sleep disorders to depression, cardiovascular diseases, and cancer. This review summarizes the steps taken since melatonin's discovery by Aaron Lerner in 1958 to functionally characterize, clone, and localize receptors in mammalian tissues. The pharmacological and molecular properties of the receptors are described as well as current efforts to discover and develop ligands for treatment of a number of illnesses, including sleep disorders, depression, and cancer.

Drug-Induced Long QT Syndrome

Abstract: The drug-induced long QT syndrome is a distinct clinical entity that has evolved from an electrophysiologic curiosity to a centerpiece in drug regulation and development. This evolution reflects an increasing recognition that a rare adverse drug effect can profoundly upset the balance between benefit and risk that goes into the prescription of a drug by an individual practitioner as well as the approval of a new drug entity by a regulatory agency. This review will outline how defining the central mechanism, block of the cardiac delayed-rectifier potassium current IKr, has contributed to defining risk in patients and in populations. Models for studying risk, and understanding the way in which clinical risk factors modulate cardiac repolarization at the molecular level are discussed. Finally, the role of genetic variants in modulating risk is described.

Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling

Abstract: Heptahelical G protein-coupled receptors are the most diverse and therapeutically important family of receptors in the human genome. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by arrestin binding, which uncouples the receptor and G protein and targets the receptor for internalization. It is clear, however, that heptahelical receptor signaling does not end with desensitization. Arrestins bind a host of catalytically active proteins and serve as ligand-regulated scaffolds that recruit protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into the receptor-arrestin complex. Although many of these arrestin-bound effectors serve to modulate G protein signaling, degrading second messengers and regulating endocytosis and trafficking, other signals seem to extend beyond the receptor-arrestin complex to regulate such processes as protein translation and gene transcription. Although these findings have led to a re-envisioning of heptahelical receptor signaling, little is known about the physiological roles of arrestin-dependent signaling. In vivo, the duality of arrestin function makes it difficult to dissociate the consequences of arrestin-dependent desensitization from those that might be ascribed to arrestin-mediated signaling. Nonetheless, recent evidence generated using arrestin knockouts, G protein-uncoupled receptor mutants, and arrestin pathway-selective "biased agonists" is beginning to reveal that arrestin signaling plays important roles in the retina, central nervous system, cardiovascular system, bone remodeling, immune system, and cancer. Understanding the signaling roles of arrestins may foster the development of pathway-selective drugs that exploit these pathways for therapeutic benefit.

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

Abstract: Diverse brain insults, including traumatic brain injury, stroke, infections, tumors, neurodegenerative diseases, and prolonged acute symptomatic seizures, such as complex febrile seizures or status epilepticus (SE), can induce “epileptogenesis,” a process by which normal brain tissue is transformed into tissue capable of generating spontaneous recurrent seizures. Furthermore, epileptogenesis operates in cryptogenic causes of epilepsy. In view of the accumulating information about cellular and molecular mechanisms of epileptogenesis, it should be possible to intervene in this process before the onset of seizures and thereby either prevent the development of epilepsy in patients at risk or increase the potential for better long-term outcome, which constitutes a major clinical need. For identifying pharmacological interventions that prevent, interrupt or reverse the epileptogenic process in people at risk, two groups of animal models, kindling and SE-induced recurrent seizures, have been recommended as potentially useful tools. Furthermore, genetic rodent models of epileptogenesis are increasingly used in assessing antiepileptogenic treatments. Two approaches have been used in these different model categories: screening of clinically established antiepileptic drugs (AEDs) for antiepileptogenic or disease-modifying potential, and targeting the key causal mechanisms that underlie epileptogenesis. The first approach indicated that among various AEDs, topiramate, levetiracetam, carisbamate, and valproate may be the most promising. On the basis of these experimental findings, two ongoing clinical trials will address the antiepileptogenic potential of topiramate and levetiracetam in patients with traumatic brain injury, hopefully translating laboratory discoveries into successful therapies. The second approach has highlighted neurodegeneration, inflammation and up-regulation of immune responses, and neuronal hyperexcitability as potential targets for antiepileptogenesis or disease modification. This article reviews these areas of progress and discusses the challenges associated with discovery of antiepileptogenic therapies.

International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid Receptor Nomenclature

Abstract: Lysophospholipids are cell membrane-derived lipids that include both glycerophospholipids such as lysophosphatidic acid (LPA) and sphingoid lipids such as sphingosine 1-phosphate (S1P). These and related molecules can function in vertebrates as extracellular signals by binding and activating G protein-coupled receptors. There are currently five LPA receptors, along with a proposed sixth (LPA1-LPA6), and five S1P receptors (S1P1-S1P5). A remarkably diverse biology and pathophysiology has emerged since the last review, driven by cloned receptors and targeted gene deletion (“knockout”) studies in mice, which implicate receptor-mediated lysophospholipid signaling in most organ systems and multiple disease processes. The entry of various lysophospholipid receptor modulatory compounds into humans through clinical trials is ongoing and may lead to new medicines that are based on this signaling system. This review incorporates IUPHAR Nomenclature Committee guidelines in updating the nomenclature for lysophospholipid receptors (http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=36).

Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes

Abstract: For many years seven transmembrane domain G protein-coupled receptors (GPCRs) were thought to exist and function exclusively as monomeric units. However, evidence both from native cells and heterologous expression systems has demonstrated that GPCRs can both traffic and signal within higher-order complexes. As for other protein-protein interactions, conformational changes in one polypeptide, including those resulting from binding of pharmacological ligands, have the capacity to alter the conformation and therefore the response of the interacting protein(s), a process known as allosterism. For GPCRs, allosterism across homo- or heteromers, whether dimers or higher-order oligomers, represents an additional topographical landscape that must now be considered pharmacologically. Such effects may offer the opportunity for novel therapeutic approaches. Allosterism at GPCR heteromers is particularly exciting in that it offers additional scope to provide receptor subtype selectivity and tissue specificity as well as fine-tuning of receptor signal strength. Herein, we introduce the concept of allosterism at both GPCR homomers and heteromers and discuss the various questions that must be addressed before significant advances can be made in drug discovery at these GPCR complexes.

Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?

Abstract: This topically limited review explores the relationship between the immune system and insulin-like growth factors (IGF-I and IGF-II) and the proteins through which they act, including IGF-I receptor (IGF-IR) and the IGF-I binding proteins. The IGF/IGF-IR pathway plays important and diverse roles in tissue development and function. It regulates cell cycle progression, apoptosis, and the translation of proteins. Many of the consequences ascribed to IGF-IR activation result from its association with several accessory proteins that are either identical or closely related to those involved in insulin receptor signaling. Relatively recent awareness that IGF-I and IGF-IR regulate immune function has cast this pathway in an unexpected light; it may represent an important switch governing the quality and amplitude of immune responses. IGF-I/IGF-IR signaling may also participate in the pathogenesis of autoimmune diseases, although its relationship with these processes seems complex and relatively unexplored. On the one hand, IGF-I seems to protect experimental animals from developing insulin-deficient diabetes mellitus. In contrast, activating antibodies directed at IGF-IR have been detected in patients with Graves' disease, where the receptor is overexpressed by multiple cell types. The frequency of IGF-IR+ B and T cells is substantially increased in patients with that disease. Potential involvement of IGF-I and IGF-IR in the pathogenesis of autoimmune diseases suggests that this pathway might constitute an attractive therapeutic target. IGF-IR has been targeted in efforts directed toward drug development for cancer, employing both small-molecule and monoclonal antibody approaches. These have been generally well-tolerated. Recognizing the broader role of IGF-IR in regulating both normal and pathological immune responses may offer important opportunities for therapeutic intervention in several allied diseases that have proven particularly difficult to treat.

International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors

Abstract: The receptor class Frizzled, which has recently been categorized as a separate group of G protein-coupled receptors by the International Union of Basic and Clinical Pharmacology, consists of 10 Frizzleds (FZD1–10) and Smoothened (SMO). The FZDs are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, whereas SMO is indirectly activated by the Hedgehog (HH) family of proteins acting on the transmembrane protein Patched (PTCH). Recent years have seen major advances in our knowledge about these seven-transmembrane-spanning proteins, including: receptor function, molecular mechanisms of signal transduction, and the receptor's role in embryonic patterning, physiology, cancer, and other diseases. Despite intense efforts, many question marks and challenges remain in mapping receptor-ligand interaction, signaling routes, mechanisms of specificity and how these molecular details underlie disease and also the receptor's important role in physiology. This review therefore focuses on the molecular aspects of WNT/FZD and HH/SMO signaling discussing receptor structure, mechanisms of signal transduction, accessory proteins, receptor dynamics, and the possibility of targeting these signaling pathways pharmacologically.

Regulation of GABA(A) receptor subunit expression by pharmacological agents.

Abstract: The gamma-aminobutyric acid (GABA) type A receptor system, the main fast-acting inhibitory neurotransmitter system in the brain, is the pharmacological target for many drugs used clinically to treat, for example, anxiety disorders and epilepsy, and to induce and maintain sedation, sleep, and anesthesia. These drugs facilitate the function of pentameric GABA(A) receptors that exhibit widespread expression in all brain regions and large structural and pharmacological heterogeneity as a result of composition from a repertoire of 19 subunit variants. One of the main problems in clinical use of GABA(A) receptor agonists is the development of tolerance. Most drugs, in long-term use and during withdrawal, have been associated with important modulations of the receptor subunit expression in brain-region-specific manner, participating in the mechanisms of tolerance and dependence. In most cases, the molecular mechanisms of regulation of subunit expression are poorly known, partly as a result of neurobiological adaptation to altered neuronal function. More knowledge has been obtained on the mechanisms of GABA(A) receptor trafficking and cell surface expression and the processes that may contribute to tolerance, although their possible pharmacological regulation is not known. Drug development for neuropsychiatric disorders, including epilepsy, alcoholism, schizophrenia, and anxiety, has been ongoing for several years. One key step to extend drug development related to GABA(A) receptors is likely to require deeper understanding of the adaptational mechanisms of neurons, receptors themselves with interacting proteins, and finally receptor subunits during drug action and in neuropsychiatric disease processes.

International Union of Basic and Clinical Pharmacology. LXXIV. Apelin Receptor Nomenclature, Distribution, Pharmacology, and Function

Abstract: A gene encoding a novel class a G-protein-coupled receptor was discovered in 1993 by homology cloning and was called APJ. It was designated an "orphan" receptor until 1998, when its endogenous ligand was identified and named apelin (for APJ endogenous ligand). Since this pairing, both apelin and its receptor have been found to have a widespread distribution in both the central nervous system and the periphery. A number of physiological and pathophysiological roles for the receptor have emerged, including regulation of cardiovascular function, fluid homeostasis, and the adipoinsular axis. This review outlines the official International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification nomenclature, designating the receptor protein as the apelin receptor, together with current knowledge of its pharmacology, distribution, and functions.

Oxidation of the Endogenous Cannabinoid Arachidonoyl Ethanolamide by the Cytochrome P450 Monooxygenases: Physiological and Pharmacological Implications

Abstract: Arachidonoyl ethanolamide (anandamide) is an endogenous amide of arachidonic acid and an important signaling mediator of the endocannabinoid system. Given its numerous roles in maintaining normal physiological function and modulating pathophysiological responses throughout the body, the endocannabinoid system is an important pharmacological target amenable to manipulation directly by cannabinoid receptor ligands or indirectly by drugs that alter endocannabinoid synthesis and inactivation. The latter approach has the possible advantage of more selectivity, thus there is the potential for fewer untoward effects like those that are traditionally associated with cannabinoid receptor ligands. In that regard, inhibitors of the principal inactivating enzyme for anandamide, fatty acid amide hydrolase (FAAH), are currently in development for the treatment of pain and inflammation. However, several pathways involved in anandamide synthesis, metabolism, and inactivation all need to be taken into account when evaluating the effects of FAAH inhibitors and similar agents in preclinical models and assessing their clinical potential. Anandamide undergoes oxidation by several human cytochrome P450 (P450) enzymes, including CYP3A4, CYP4F2, CYP4X1, and the highly polymorphic CYP2D6, forming numerous structurally diverse lipids, which are likely to have important physiological roles, as evidenced by the demonstration that a P450-derived epoxide of anandamide is a potent agonist for the cannabinoid receptor 2. The focus of this review is to emphasize the need for a better understanding of the P450-mediated pathways of the metabolism of anandamide, because these are likely to be important in mediating endocannabinoid signaling as well as the pharmacological responses to endocannabinoid-targeting drugs.

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

Abstract: The hedgehog (Hh)/glioma-associated oncogene (GLI) signaling network is among the most important and fascinating signal transduction systems that provide critical functions in the regulation of many developmental and physiological processes. The coordinated spatiotemporal interplay of the Hh ligands and other growth factors is necessary for the stringent control of the behavior of diverse types of tissue-resident stem/progenitor cells and their progenies. The activation of the Hh cascade might promote the tissue regeneration and repair after severe injury in numerous organs, insulin production in pancreatic β-cells, and neovascularization. Consequently, the stimulation of the Hh pathway constitutes a potential therapeutic strategy to treat diverse human disorders, including severe tissue injuries; diabetes mellitus; and brain, skin, and cardiovascular disorders. In counterbalance, a deregulation of the Hh signaling network might lead to major tissular disorders and the development of a wide variety of aggressive and metastatic cancers. The target gene products induced through the persistent Hh activation can contribute to the self-renewal, survival, migration, and metastasis of cancer stem/progenitor cells and their progenies. Moreover, the pivotal role mediated through the Hh/GLI cascade during cancer progression also implicates the cooperation with other oncogenic products, such as mutated K-RAS and complex cross-talk with different growth factor pathways, including tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), Wnt/β-catenin, and transforming growth factor-β (TGF-β)/TGF-β receptors. Therefore, the molecular targeting of distinct deregulated gene products, including Hh and EGFR signaling components and other signaling elements that are frequently deregulated in highly tumorigenic cancer-initiating cells and their progenies, might constitute a potential therapeutic strategy to eradicate the total cancer cell mass. Of clinical interest is that these multitargeted approaches offer great promise as adjuvant treatments for improving the current antihormonal therapies, radiotherapies, and/or chemotherapies against locally advanced and metastatic cancers, thereby preventing disease relapse and the death of patients with cancer.

International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin Receptor Nomenclature, Distribution, and Function

Abstract: Kisspeptins are members of the Arg-Phe amide family of peptides, which have been identified as endogenous ligands for a G-protein-coupled receptor encoded by a gene originally called GPR54 (also known as AXOR12 or hOT7T175). After this pairing, the gene has been renamed KISS1R. The International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification recommends that the official name for the receptor is the kisspeptin receptor to follow the convention of naming the receptor protein after the endogenous ligand. The endogenous ligand was initially called metastin, after its role as a metastasis suppressor, and is now referred to as kisspeptin-54 (KP-54), a C-terminally amidated 54-amino acid peptide cleaved from the 145-amino acid gene product. Shorter C-terminal cleavage fragments [KP-14, KP-13 and KP-10 (the smallest active fragment)] are also biologically active. Both receptor and peptide are widely expressed in human, rat, and mouse; the receptor sequence shares more than 80% homology in these species. Activation of the kisspeptin receptor by kisspeptin is via coupling to Gq/11 and the phospholipase C pathway, causing Ca2+ mobilization. Mutations in the KISS1R gene result in hypogonadotropic hypogonadotropism, and targeted disruption of Kiss1r in mice reproduces this phenotype, which led to the discovery of the remarkable ability of the kisspeptin receptor to act as a molecular switch for puberty. In addition to regulating the reproductive axis, the kisspeptin receptor is also implicated in cancer, placentation, diabetes, and the cardiovascular system.

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

Abstract: The central nervous system mediates energy balance (energy intake and energy expenditure) in the body; the hypothalamus has a key role in this process. Recent evidence has demonstrated an important role for hypothalamic malonyl CoA in mediating energy balance. Malonyl CoA is generated by the carboxylation of acetyl CoA by acetyl CoA carboxylase and is then either incorporated into long-chain fatty acids by fatty acid synthase, or converted back to acetyl-CoA by malonyl CoA decarboxylase. Increased hypothalamic malonyl CoA is an indicator of energy surplus, resulting in a decrease in food intake and an increase in energy expenditure. In contrast, a decrease in hypothalamic malonyl CoA signals an energy deficit, resulting in an increased appetite and a decrease in body energy expenditure. A number of hormonal and neural orexigenic and anorexigenic signaling pathways have now been shown to be associated with changes in malonyl CoA levels in the arcuate nucleus (ARC) of the hypothalamus. Despite compelling evidence that malonyl CoA is an important mediator in the hypothalamic ARC control of food intake and regulation of energy balance, the mechanism(s) by which this occurs has not been established. Malonyl CoA inhibits carnitine palmitoyltransferase-1 (CPT-1), and it has been proposed that the substrate of CPT-1, long-chain acyl CoA(s), may act as a mediator(s) of appetite and energy balance. However, recent evidence has challenged the role of long-chain acyl CoA(s) in this process, as well as the involvement of CPT-1 in hypothalamic malonyl CoA signaling. A better understanding of how malonyl CoA regulates energy balance should provide novel approaches to targeting intermediary metabolism in the hypothalamus as a mechanism to control appetite and body weight. Here, we review the data supporting an important role for malonyl CoA in mediating hypothalamic control of energy balance, and recent evidence suggesting that targeting malonyl CoA synthesis or degradation may be a novel approach to favorably modify appetite and weight gain.

Correction to Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling

Abstract: Heptahelical G protein-coupled receptors are the most diverse and therapeutically important family of receptors in the human genome. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by arrestin binding, which uncouples the receptor and G protein and targets the receptor for internalization. It is clear, however, that heptahelical receptor signaling does not end with desensitization. Arrestins bind a host of catalytically active proteins and serve as ligand-regulated scaffolds that recruit protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into the receptor-arrestin complex. Although many of these arrestin-bound effectors serve to modulate G protein signaling, degrading second messengers and regulating endocytosis and trafficking, other signals seem to extend beyond the receptor-arrestin complex to regulate such processes as protein translation and gene transcription. Although these findings have led to a re-envisioning of heptahelical receptor signaling, little is known about the physiological roles of arrestin-dependent signaling. In vivo, the duality of arrestin function makes it difficult to dissociate the consequences of arrestin-dependent desensitization from those that might be ascribed to arrestin-mediated signaling. Nonetheless, recent evidence generated using arrestin knockouts, G protein-uncoupled receptor mutants, and arrestin pathway-selective “biased agonists” is beginning to reveal that arrestin signaling plays important roles in the retina, central nervous system, cardiovascular system, bone remodeling, immune system, and cancer. Understanding the signaling roles of arrestins may foster the development of pathway-selective drugs that exploit these pathways for therapeutic benefit.