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Metabotropic glutamate receptors comprise a diverse family of G protein-coupled receptors that are critical for regulating normal neuronal function in the central nervous system (CNS). The heterogeneous distribution and diverse physiologic roles of the various mGluR subtypes make them highly attractive targets for the treatment of a number of neurologic and psychiatric disorders. The discovery of subtype-selective ligands for these receptors has provided the tools to support a number of preclinical studies, suggesting the tremendous therapeutic potential that lies in the ability selectively to modulate a specific mGluR subtype. In the last few years, a major milestone in the field was achieved with the first selective mGluR ligands entering into clinical development and demonstrating efficacy in the treatment of anxiety disorders. In addition to the discovery of selective, direct-acting mGluR ligands, a novel class of mGluR-selective ligands has recently emerged. These allosteric modulators, which act through nontraditional binding sites on the mGluRs, may exhibit even greater subtype selectivity than orthosteric ligands. Furthermore, because they modulate mGluRs in an activity-dependent manner, it is possible that allosteric activators of mGluRs will be less likely to induce adverse effects or promote receptor desensitization. This chapter summarizes the critical studies that have contributed to the validation of mGluRs as therapeutic targets for the treatment of a number of CNS disorders and describes progress thus far in identifying and developing novel mGluR subtype-selective compounds. [ABSTRACT FROM AUTHOR]

Long-term potentiation (LTP) and long-term depression (LTD) are important forms of synaptic plasticity thought to underlie many brain processes such as those involved in brain development, memory, and drug addiction. The metabotropic glutamate receptors (mGluRs) are capable of inducing both LTP and LTD, and also of modulating the induction of plasticity initiated by other receptor systems. Although early work focused on the role of mGluRs in LTP, the precise nature of their involvement in LTP induction remains unclear. However, there is considerable evidence that activation of mGluRs can induce LTD in numerous brain regions. This chapter reviews the evidence for mGluR involvement in LTP induction and discusses the roles of mGluRs in LTD. In particular it describes the signaling pathways and expression mechanisms of two prominent forms of LTD—those seen in the CA1 region of the hippocampus and the cerebellum. [ABSTRACT FROM AUTHOR]

G protein-coupled group III metabotropic glutamate receptors (mGluRs) include four subtypes that are negatively coupled to adenylyl cyclase (mGluRs 4, 7, and 8) or positively to a cGMP phosphodiesterase (mGluR6). Typically, they exert inhibitory influences on neuronal activity. This chapter reviews the characteristics of group III mGluRs and their normal functions and role in nervous system disorders. The therapeutic potential of group III mGluRs resides in their antiepileptic (mGluRs 4 and 7), neuroprotective (mGluRs 4, 7, and 8), anti-parkinsonian (mGluRs 4 and 7), anxiolytic (mGluR4), and analgesic effects. However, possible side effects may need to be considered because group III mGluRs can inhibit normal synaptic transmission and memory processes, and mGluR6 is important for visual transmission. This chapter emphasizes that the analysis of the role of individual group III mGluR subtypes is required to determine their potential therapeutic value. [ABSTRACT FROM AUTHOR]

The group II metabotropic glutamate (mGlu2 and mGlu3) receptors are among the minority of glutamate receptors that primarily inhibit synaptic transmission by coupling to Gio, inhibiting adenylate cyclase and potassium channels. Our understanding of their physiologic role has advanced considerably with the discovery of systemically active and selective agonists, antagonists, and, most recently, subtype-selective allosteric modulators. The mGlu2/3 agonists, such as LY354740 (and its prodrug LY544344), show activity in a number of preclinical models of anxiety, psychosis, and drug abuse and as neuroprotectants. The anxiolytic actions of group II agents have subsequently been confirmed in humans, and represent an exciting breakthrough in the glutamate field. Emerging preclinical results with mGlu2/3 antagonists and potentiators of the mGlu2 receptor indicate that, despite a presynaptic localization distal to the synaptic active zone, significant glutamatergic tone can occur under some physiologic conditions. This chapter describes some mGlu2/3-selective pharmacologic tools, briefly discusses the different synaptic and glial localizations, and notes how these unique receptors may regulate synaptic transmission. [ABSTRACT FROM AUTHOR]

Interest in the structures of the metabotropic glutamate receptors continues to increase for a variety of reasons, including the fact that they are now established drug targets and are linked to a wide spectrum of physiologic processes both within and outside the central nervous system. This chapter summarizes our knowledge of the structures of the eight receptor subtypes, including the alternatively spliced forms, and the experimental approaches that have been used to study them. The large size and multiple domains of these proteins are conducive to further advances in the development of drugs for potential therapeutic use, and for basic research directed toward elucidating the intrinsic signaling mechanisms of these complex molecules. Increasingly detailed analyses of protein-protein interactions between the metabotropic glutamate receptors and other signaling molecules will also contribute to a deeper understanding of how this class of receptors and related G protein-coupled receptors, function at the molecular level within biologic membranes in vivo. [ABSTRACT FROM AUTHOR]

Many potentially neuroprotective drugs have failed in human clinical trials because of side effects that cause normal brain function to become compromised. An important example concerns antagonists of the N-methyl-D-aspartate type of glutamate receptor (NMDAR). Glutamate receptors are essential to the normal function of the central nervous system. However, their excessive activation by excitatory amino acids such as glutamate is thought to contribute to neuronal damage in many neurologic disorders ranging from acute hypoxic-ischemic brain injury to chronic neurodegenerative diseases such as Alzheimer disease, Parkinson disease, Huntington disease, HIV-associated dementia, multiple sclerosis, glaucoma, and amyotrophic lateral sclerosis. The dual role of NMDARs in particular for normal and abnormal functioning of the nervous system imposes important constraints on possible therapeutic strategies aimed at ameliorating neurologic diseases. Blockade of excessive NMDAR activity must therefore be achieved without interference with its normal function. In general, NMDAR antagonists can be categorized pharmacologically according to the site of action on the receptor-channel complex. These include drugs acting at the agonist (NMDA) or coagonist (glycine) sites, channel pore, and modulatory sites, such as the S-nitrosylation site, where nitric oxide (NO) reacts with critical cysteine thiol groups. Because glutamate is thought to be the major excitatory transmitter in the brain, generalized inhibition of a glutamate receptor subtype like the NMDAR causes side effects that clearly limit the potential for clinical applications. Both competitive NMDA and glycine antagonists, From: The Receptors: The Glutamate Receptors even though they are effective in preventing glutamate-mediated neurotoxicity, will cause generalized inhibition of NMDAR activities and thus have failed in many clinical trials. Open-channel block, a form of uncompetitive antagonism, is the most appealing strategy for therapeutic intervention during excessive NMDAR activation because this action of blockade; requires prior activation of the receptor. This property, in theory, leads to a higher degree of channel blockade in the presence of excessive levels of glutamate and little blockade at relatively lower levels, for example, during physiologic neurotransmission. As an alternative strategy, genetic manipulation of NR3 subunits can reduce glutamateinduced currents and Ca2+ influx through NMDARs without completely blocking their activation. Based on this molecular strategy of action, this chapter reviews the logical process that was applied over the last decade to develop memantine as the first clinically tolerated yet effective agent against NMDAR-mediated neurotoxicity. Phase 3 (final) clinical trials have shown that memantine is effective in treating moderateto- severe Alzheimer's disease while being well tolerated. Memantine is also in trials for additional neurologic disorders, including other forms of dementia, glaucoma, and severe neuropathic pain. In addition, taking advantage of memantine's preferential binding to open channels and the act that excessive NMDAR activity can be downregulated by S-nitrosylation, combinatorial drugs called NitroMemantine have recently been developed. These drugs use memantine as a homing signal to target NO to hyperactivated NMDARs to avoid systemic side effects of NO such as hypotension (low blood pressure). These second-generation memantine derivatives are designed as pathologically activated therapeutics, and in preliminary studies they appear to have even greater neuroprotective properties than memantine. [ABSTRACT FROM AUTHOR]

Ampakines are small synthetic compounds that cross the blood-brain barrier and enhance fast excitatory synaptic responses mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. Their binding site has been identified and shown to be appropriately located for slowing receptor deactivation and desensitization, the two processes that terminate excitatory transmission. After reviewing these mechanisms, this paper takes up the question of why ampakines, although targeted at receptors found throughout the brain, produce surprisingly discrete behavioral effects. Three processes are hypothesized to be involved: (1) the facilitation of excitatory inputs to inhibitory interneurons balances the effects of ampakines on glutamatergic neurons; (2) the compounds have preferences for receptor subtypes and thus for particular brain regions; and (3) the potency of the ampakines scales positively with the complexity of brain networks. The discrete effects of the drugs raise the possibility of using them in the treatment of psychiatric disorders. Ampakines improve performance of complex behaviors in rodents and primates, accelerate learning across a diverse array of tests, and have positive effects in animal models of schizophrenia, attention deficit hyperactivity disorder (ADHD), and depression. Improved memory scores and a reduction in ADHD symptoms are also reported in studies with human subjects. It is hypothesized that these behavioral effects reflect facilitation of communication within cortex, a lowered threshold for the induction of long-term potentiation, and enhanced cortical regulation of lower brain systems. Finally, ampakines upregulate the production of brain-derived neurotrophic factor (BDNF). Experimental work prompted by this observation indicates that chronic ampakine treatments cause sizeable improvements in animal models of Parkinson disease, excitotoxic brain damage, and age-related losses of synaptic plasticity. [ABSTRACT FROM AUTHOR]

Recent structural and functional studies of ionotropic glutamate receptors (iGluRs) have begun to offer rare insight into the structure-function relationship for an integral membrane protein. In particular, advances in our understanding of iGluR structure are providing an opportunity to interpret functional work in terms of potential conformational changes. Moreover, working hypotheses derived from structural insight offer an opportunity to enrich and guide functional studies. This chapter summarizes knowledge of glutamate receptor structure, with an emphasis on how it has shaped our functional understanding of these receptors. [ABSTRACT FROM AUTHOR]

More than 30 years have elapsed since the publication of the first reports of long-term potentiation by Bliss and Lomo (1973) and Bliss and Gardner-Medwin (1973). These two reports ushered in an exciting new era in which measurable persistent changes in synaptic strength were posited as substrates for learning and memory. Since that time, the study of long-term mechanisms of synaptic plasticity have arguably been one of the most intensely and perhaps the most rewarding fields of the neurosciences, casting important light on the nature of synaptic transmission and the events associated with the strengthening or weakening of synapses. Indeed, although once principally studied at excitatory glutamatergic synapses within the hippocampus and cortical formations, mechanisms of synaptic plasticity are observed at a myriad of synaptic connections throughout the mammalian central nervous system. Moreover, although many of these synapses share common mechanisms of plasticity, the last decade has seen an explosion in our understanding of plasticities peculiar to one synapse or another. This chapter does not attempt to cover all of these divergent mechanisms but instead focuses on those mechanisms of long-term potentiation (LTP) and depression (LTD) most commonly found within the hippocampal formation. A large portion of this review covers N-methyl-\fontsize77\selectfont D-aspartate-receptor-dependent LTP and LTD, the two most commonly studied forms of cortical plasticity; however, it also addresses plasticity mechanisms at other hippocampal synapses that have not enjoyed the same intensity of investigation but are worthy of attention. [ABSTRACT FROM AUTHOR]

No endogenous ligands have been identified for the delta subfamily of ionotropic glutamate receptors (GluRδ1 and GluRδ2). Nevertheless, GluRδ2 plays indispensable roles in cerebellar functions; mice that lack the GluRδ2 gene display ataxia and impaired motor-related learning tasks. Recent studies of mutant mice, such as lurcher, hotfoot, and GluRδ2- knockout mice, have provided clues to the structure and function of GluRδ2. In particular, morphologic and electrophysiologic analyses of hotfoot and GluRδ2-knockout mice have demonstrated a unique role of GluRδ2 in synapse formation and its maintenance. In addition, an antibody specific for GluRδ2′s extracellular N-terminal indicated its direct role in controlling cerebellar long-term depression. These results suggest that GluRδ2 regulates distinct s pathways involved in synapse formation and synaptic plasticity. [ABSTRACT FROM AUTHOR]

Kainate receptors are glutamate-gated ion channels whose functional roles in the brain have been only poorly understood until recently. A picture has developed over the last decade of kainate receptors as subtle actors in neurotransmission; they modulate excitatory and inhibitory transmission and neuronal excitability and generate small but prolonged depolarizations at a subset of postsynaptic sites. This chapter reviews a variety of aspects of kainate receptor function, including their structure, biophysical function, and activities in (and out) of synapses in the mammalian brain. [ABSTRACT FROM AUTHOR]

One of the major classes of ionotropic glutamate receptors is made up of the N-methyl-D-aspartate (NMDA) receptors, which require two agonists, glycine and glutamate, for activation and can pass calcium ions that may mediate synaptic and neuronal plasticity. They are formed from complexes made by various combinations of the subunits NR1 (with eight isoforms), NR2A-D, and NR3A-B and are found in most neurons of the brain and in various other cells. During development, generally NMDA receptors with NR2B, NR2D, and NR3A are abundant and decrease during maturation, whereas those with NR2A and NR2C increase. The function of NMDA receptors has been explored with a wide range of in vitro and in vivo studies, employing both recombinant gene constructs and native receptors. NMDA receptor subunits contain various motifs that control retention in the endoplasmic reticulum and trafficking through Golgi and other organelles to reach the cell membrane. Association of NMDA receptors with PDZ domain-containing proteins such as PSD-95 and SAP102 may be particularly important to trafficking and/or stabilization and function on the cell membrane. NMDA receptors on the cell membrane are sequestered mainly to the postsynaptic membrane of synapses, but some populations remain in extrasynaptic domains, especially those receptors that contain NR2B or NR2D. [ABSTRACT FROM AUTHOR]

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMP ARs) are glutamate-gated ion channels. They are the neurotransmitter receptors that mediate the great majority of fast excitatory synaptic transmission in the mammalian brain and are found throughout the animal kingdom in organisms as diverse as rodents, honeybees, nematode worms, and humans. They are absolutely critical for brain function; for example, infusion of a selective AMPAR antagonist into the rat hippocampus in vivo completely silences excitatory transmission in that region (1). AMPARs are also required for adaptive changes in the brain, mediating the expression of forms of long-term and short-term synaptic plasticity that are believed to underlie learning and memory, development, and certain neurologic diseases (2-5). Thus, AMPARs play a central role in brain function, and consequently there is great interest in the development of novel therapies directed at modulating AMPAR function for treatment of neurologic disorders, such as Alzheimer disease and stroke. [ABSTRACT FROM AUTHOR]

At present, the only therapeutic agent in current use that is known to exert its effects through the GABA-B receptor is baclofen, the β-chlorophenyl analog of GABA. This compound is used extensively as a centrally active muscle relaxant, but it has been shown clinically to exert additional effects, including analgesia, suppression of drug addiction, and cessation of chronic cough. Basic research indicates that there may be many other applications not only for agonists, but also antagonists at the GABA-B receptor, and this chapter seeks to examine the potential significance of these and also of allosteric modulators for the receptor, which have been recognized during the past 5 yr. GABA-B receptors have been implicated in neuronal processing in many brain regions and there is considerable evidence for their pathological involvement in various diseases of the central nervous system, such as absence epilepsy, depression, and even in the etiology of nicotine dependency in humans. Novel chemical entities will surely be the key to exploiting this receptor. At present, the only agonist (baclofen) in the clinic frequently produces unwanted side effects, and this clearly limits its usage. There are no antagonists in clinical therapy, although trials for cognition deficits are underway. Metabotropic receptors, of which the GABA-B receptor is a member, provide most of the targets for our currently used therapeutic agents; thus, there seems to be every reason to believe that the rewards for discovering clinically available GABA-B receptor ligands could be high. [ABSTRACT FROM AUTHOR]

γ-Aminobutyric acid B (GABAB) receptors are the G protein-coupled receptors for the inhibitory neurotransmitter GABA. Cloning efforts revealed that functional GABAB receptors can be assembled from the products of the GABAB1 and GABAB2 genes. However, cloned receptors do not exhibit the reported functional and pharmacological diversity of native receptors, which led to speculations about the existence of additional GABAB receptor genes. Several groups now have generated mice with ablations in the GABAB1 and GABAB2 genes, which allowed studying the contributions of cloned gene products to pre- and postsynaptic GABAB functions. In this chapter, we review the phenotypes of GABAB knockout mice and discuss how genetic experiments have contributed to our current understanding of the GABAB receptor system. [ABSTRACT FROM AUTHOR]

Functional γ-aminobutyric acid (GABAB) receptors are formed by the association of GABABR1 and GABABR2, two closely related subunits belonging to the G protein coupled receptor superfamily. An increasing number of reports have now uncovered that GABAB receptors display unique functional properties, including unusual activation and inactivation mechanisms following binding of agonists. In this chapter the focus will be on nonclassical aspects of GABAB receptor phosphorylation, desensitization, downregulation, signaling, and association with a variety of protein partners. In addition, the extent to which the heterodimeric structure of the receptor contributes to establish these unusual properties will be discussed. [ABSTRACT FROM AUTHOR]

Nearly 10 yr have passed since the authors review "Chemistry of GABAB Modulators" appeared in the book "The GABA Receptors," 2nd edition, edited by S. J. Enna and N. G. Bowery, Humana Press, Totowa, 1997 (1). In this update the authors wish to outline only new developments not covered in the 1997 paper. Baclofen, synthesized for the first time in September 1962, is still the only γ-aminobutyric acid (GABAB)-receptor agonist marketed for the treatment of spasticity and trigeminal neuralgia. It is fascinating to learn how many highly competent chemists devised manifold and elegant synthetic procedures for either racemic or (R)-(−)-baclofen and the structurally closely related potent antidepressant (R)-(−)-Rolipram, a selective phosphodiesterase-4 inhibitor. The new syntheses published after 1996 are listed in alphabetical order (2-16). Very recently a prodrug of (R)-(−)-baclofen (Fig. 1) was described which enhanced the oral bioavailability in Cynomolgus monkeys to more than 80% (17). It is planned to test this prodrug in clinical trials for the treatment of spasticity and gastroesophageal reflux disease. [ABSTRACT FROM AUTHOR]

The γ-aminobutyric acid (GABA) neurotransmitter acting through ionotropic and metabotropic receptor classes exerts the major inhibitory control in the central nervous system. Therapeutic agents targeting GABA receptors (GABA-R), such as benzodiazepines and baclofen, are used to treat many nervous system conditions, including anxiety and spasticity. The subunit composition of GABA-Rs at the cell surface plays a critical role in determining their physiological and pharmacological properties, and alteration of GABA-R subunit expression has been associated with a number of diseases including schizophrenia, temporal lobe epilepsy, and alcoholism. The ionotropic type A GABA receptor (GABAAR) and type C GABA receptor (GABACR) are pentameric complexes that comprise a ligand gated chloride channel. The metabotropic type B GABA receptor (GABABR) is a heterodimer that couples G protein-signaling to GABA binding. There are eight classes of ionotropic receptor subunits and only two metabotropic receptor subunit classes. Most of the GABAAR subunit genes are localized in syntenic β-α-γ gene clusters on four chromosomes but the two GABABR genes are localized on distinct chromosomes. Control over subunit expression in different brain regions and during development is orchestrated at the genomic level by the use of multiple promoter regions and through the alternative splicing of GABA-R subunit RNAs. This chapter examines current GABA-R research relevant to the many levels of control over receptor gene regulation and cell surface receptor expression that may be relevant to both health and disease. [ABSTRACT FROM AUTHOR]

Ligands that act at γ-aminobutyric type A (GABAA) receptors, in particular the benzodiazepines and related drugs, have broad clinical use but also the liability for abuse and dependence. Recent epidemiological data suggest that abuse of benzodiazepine-type drugs may be on the upswing, with a shift from primary misuse of benzodiazepines by people in a therapeutic setting to use by younger people engaging in recreational abuse. Laboratory findings suggest that benzodiazepine-type drugs have reinforcing effects both in human and non-human subjects. However, benzodiazepine-type drugs appear to have lower reinforcing effectiveness compared to other drugs of abuse, such as psychomotor stimulants. Recent research has begun to explore the role of GABAA receptor subtypes in the reinforcing effects of benzodiazepine-type drugs, and unlike other behavioral effects (e.g., motor coordination deficits); reinforcing effects are not easily attributed to a single receptor subtype. Perhaps the most firm conclusion that can be made at this point is that stimulation of GABAA receptors containing α1 subunits (α1GABAA receptors) is not necessary for self-administration of benzodiazepine-type compounds. Benzodiazepine use also is associated with physical dependence, characterized by a withdrawal syndrome. In both human and non-human subjects, this withdrawal syndrome is considered to be intermediate in severity. Preliminary results suggest that compounds with selectivity for α2GABAA, α3GABAA, and/or α5GABAA receptors do not induce physical dependence. As with reinforcing effects, systematic studies with selective compounds having relatively high intrinsic efficacy at particular subtypes should shed light on theses important mechanistic issues. [ABSTRACT FROM AUTHOR]

Idiopathic generalized epilepsies (IGEs) are characterized by absence, myoclonic, and/or primary generalized tonic-clonic seizures in the absence of structural brain abnormalities and are believed to have a genetic basis. Mutations in γ-aminobutyric acid (GABAA) receptor γ2-, α1-, and δ-subunits have been associated with different IGE syndromes, and all of the γ2-subunit mutations are also associated with febrile seizures. Here, mutations in GABAA receptor γ2-, α1-, and δ-subunits that have been associated with different IGE syndromes will be reviewed and the basis for the defect in GABAergic inhibition associated with febrile seizures will be explored. These mutations have been shown to alter GABAA receptor gating, expression, and/or trafficking of the receptor to the cell surface, all pathophysiological mechanisms that result in reduced GABA-evoked currents that, in turn, would cause neuronal disinhibition in neurons and thus predispose affected patients to manifest afebrile and febrile seizures. [ABSTRACT FROM AUTHOR]

γ-Aminobutyric acid A (GABAA) receptor subunit multiplicity results in the generation of diverse receptor subtypes with distinct biophysical and pharmacological properties. These receptor subtypes show different subcellular targeting and can be activated by GABA in different ways, with different functional outcomes. Synaptic receptors underlie brief postsynaptic currents, whereas high-affinity, largely extrasynaptic, receptors generate a "tonic" conductance. These differences have implications for our understanding of normal brain function and the rational design of therapeutic agents. [ABSTRACT FROM AUTHOR]

γ-Aminobutyric acid (GABAA) receptors are the major inhibitory neurotransmitter receptors in the brain and are the site of action of many clinically important drugs. They are made up of five subunits that can belong to eight different subunit classes. Depending on their subunit composition these receptors exhibit distinct pharmacological and electrophysiological properties. The distinct but overlapping regional and cellular distribution of these subunits gives rise to the formation of a large number of GABAA-receptor subtypes, only a few of which so far have been unequivocally identified in the brain. Recent homology modeling of the structure of the extracellular and transmembrane domain of GABAA receptors for the first time provided a glimpse on the three-dimensional organization of this receptor, and placed different protein segments that have been shown to be of functional importance into a "region in space" and into defined neighboring relations. The models obtained could explain experimental observations and propose the location of putative drug-binding sites. They can be now used to design experiments for clarification of pharmacological and structural questions as well as to shed light on conformational changes during binding of agonist, gating, and allosteric modulation of these receptors. [ABSTRACT FROM AUTHOR]

γ-Aminobutyric acid receptors (GABAA Rs) are the principal receptors that mediate neural inhibition in the brain. Changes in the function of GABAergic transmission are implicated in activity-dependent adaptation of neural excitability. Of particular interest are mechanisms that control the size of the postsynaptic GABAA-receptor pool, a major determinant of synaptic strength. Mechanisms of trafficking of postsynaptic GABAA Rs contribute to regulation of inhibitory synaptic transmission in response to changes in neural activity and extracellular stimuli. This review summarizes current information available on the receptor structures relevant for trafficking of GABAA Rs, the molecular composition of the submembrane cytoskeleton of inhibitory synapses, and the receptor interacting proteins that regulate the localization and trafficking of postsynaptic GABAA Rs during exocytosis, lateral diffusion and endocytic recycling, and degradative pathways. [ABSTRACT FROM AUTHOR]

Oscillatory activities are hallmarks of neuronal network functions. They contribute to information processing in a multitude of brain activities including cognitive functions. A key requirement for the generation of network oscillations is regular and synchronized neuronal activity. The temporal structure and spatial coherence of network oscillations is largely controlled by GABAergic interneurons. To provide the appropriate response characteristics the synaptic specialization of these interneurons includes an extensive diversity of GABAA receptors. The cell- and domain-specific location of these receptor subtypes offers the possibility to gain functional insights into the role of defined neuronal circuits. Pharmacologically, neurons operating with α1 GABAA receptors mediate sedation while the small population of α2GABAA receptors largely mediates anxiolysis. Schizophrenia-related phenotypes can be ameliorated through α3GABAA receptors. Memory and learning are enhanced by diminishing α5GABAA receptor function. Thus, by targeting selective neuronal circuits GABAA receptor subtypes provide a new circuit-specific GABA pharmacology for a multitude of CNS dieases. [ABSTRACT FROM AUTHOR]

γ-Aminobutyric acid (GABA), an amino acid neurotransmitter, is widely distributed throughout the neuraxis. Two pharmacologically and molecularly distinct GABA receptors have been identified, GABAA and GABAB. GABAA receptors are pentameric ligand-gated chloride-ion channels, whereas GABAB receptors are heterodimeric G protein-coupled sites. Although GABAA receptor subtypes can display pharmacological differences, the two molecularly distinct GABAB receptors have similar substrate specificities, limiting the ability to selectively manipulate this site. Gene deletion and point mutation studies have revealed the importance of GABA receptors in neural development and function, with subtle modifications in subunit amino acid composition having profound effects on behavioral phenotype and responses to drugs. The characterization of GABAA receptors has contributed substantially to the knowledge about allosteric regulation of ligand-gated ion channels. Such information is invaluable in defining precisely the mechanisms of action of numerous drugs, such as the benzodiazepines, and toxic agents. Research on GABAB receptors has proven the existence of dimeric metabotropic receptors and has provided the chemical tools necessary for defining such systems. The characterization of the pentameric GABAA and dimeric GABAB receptors has been crucial for understanding the neurobiological basis of some nervous system disorders. Given the importance of GABA in central nervous system function, further work on its receptors is likely to yield novel therapeutics for treating a host of neurological and psychiatric conditions. [ABSTRACT FROM AUTHOR]

In this chapter, we will give a perspective of in vitro assays used in drug discovery when targeting chemokine receptors. We outline the complexity of the chemokine system and give a historical perspective on the in vitro assays and types of assays used at different stages of discovery, followed by several examples of successes and failures in clinical trials. Finally, we discuss the rationale for continuing, after several failures, to target chemokine receptors and how screening may change with the increasing evidence of dimerization of chemokine receptors. [ABSTRACT FROM AUTHOR]

Actions of chemokines and the interaction with specific receptors within the central nervous system (CNS) surpass their original defined role of leukocyte recruitment to inflamed tissues. Chemokine receptor expression by resident CNS cells is crucial for normal brain development and architectural organization, neuronal protection during inflammatory and neurotoxic challenges, and, among many others, protective mechanisms during inflammatory conditions such as multiple sclerosis. The chemokine/chemokine receptor systems involved in such significant functions include CXCR4/CXCL12, CXCR2/CXCL1, and CX3CR1/CX3CL1. In this chapter, we discuss how these receptors might contribute to modulate communication within the CNS and with peripheral elements, and we also suggest potential mechanisms of action of fractalkine and the translation of these into the understanding of microglial function during neuro-inflammatory conditions. [ABSTRACT FROM AUTHOR]

Many chemokine receptors have now been detected in a variety of malignancies. Considerable data now exist that two receptors, CXCR4 and CCR7, are widely expressed in epithelial cancers and contribute to the ability of some tumors to metastasize. Preclinical studies support a role for these receptors in mediating tumor cell migration, but other functions have also been identified including support of tumor cell proliferation in response to ligand stimulation. Less is known about the function of other chemokine receptors expressed in malignant cells, but it is likely that at least some of these also contribute to aggressive behavior. Although the specific role of each receptor is complex, it is becoming clear that these receptors may mediate metastasis to some, but not all, metastatic sites characteristic of each histologic type. Some of the site specificity is due to expression of the cognate ligand at the secondary site; however, other factors to be defined also contribute to chemokine receptor-determined metastatic patterns. [ABSTRACT FROM AUTHOR]

Angiogenesis is the process of new blood vessel growth and is a critical biological process under both physiologic and pathologic conditions. Angiogenesis can occur under physiologic conditions that include embryogenesis and the ovarian/menstrual cycle. In contrast, pathologic angiogenesis is associated with chronic inflammation/chronic fibroproliferative disorders and tumorigenesis of cancer. Similarly, aberrant angiogenesis associated with chronic inflammation/fibroproliferative disorders is analogous to neovascularization of tumorigenesis of cancer. Net angiogenesis is determined by a balance in the expression of angiogenic compared with angiostatic factors. CXC chemokines are heparin-binding proteins that display unique disparate roles in the regulation of angiogenesis. Based on their structure, CXC chemokines can be divided into two groups that either promote or inhibit angiogenesis, and they are therefore uniquely placed to regulate net angiogenesis in both physiologic and pathologic conditions. [ABSTRACT FROM AUTHOR]

Tissue fibrosis, which results in the destruction of normal organ function, is a leading cause of morbidity and mortality. Current strategies for treating fibrosis have been unsuccessful, largely because of the difficulty in distinguishing whether inflammatory or fibrogenic events sustain the progression of the disease. The causes of fibrosis are diverse regardless of the tissue involved, and the common features include the sequential recruitment of inflammatory cells, overproliferation of matrix-producing cells, and the overproduction of extracellular matrix. An excessive wound-healing response presumably represents disruption in this sequence thereby leading to a disturbance in the balance between tissue remodeling, matrix degradation, and permanent scarring. The mechanisms involved in pulmonary fibrosis also represent three sequential events characterized by an initial insult, inflammation, and tissue repair. Central to the progression of these events is the balance between a T helper 1 (Th1) and a T helper 2 (Th2) environment, in which Th2-specific signals have been shown to be immunomodulatory and profibrotic. However, the release of these Th2-specific cytokines and chemokines by both inflammatory and resident cells maintains the fibrotic response, consequently leading to fibrotic disease. Evidence from animal models and human studies have identified a number of Th1/Th2-associated chemokines and chemokine receptors as profibrotic or antifibrotic. Therefore, investigating the chemokines, chemokine receptors, and the cells that they impact is an attractive approach to identifying therapeutic targets in fibrosis. [ABSTRACT FROM AUTHOR]

There have been tremendous advances made toward our understanding of chemokine receptor biology over the past decade. Much of the research conducted in this area was fueled by discoveries that certain chemokine receptor ligands (chemokines) could specifically block human immunodeficiency virus type 1 (HIV-1) infection and that certain chemokine receptors were the long-sought coreceptors that, together with CD4, were required for the productive entry of HIV-1, HIV-2, and simian immuno-deficiency virus (SIV) isolates. In the current survey, along with the interactions of the HIV-1 envelope glycoprotein with chemokine receptors, we have focused on the relationship certain chemokine receptors have with particular cellular systems such as lipid rafts, chemokine receptor-mediated signaling, and the actin cytoskeleton; all of which appear to play roles in or influence the establishment of HIV-1 infection. We will also discuss the dichotomous effects that chemokines display at both entry and postentry levels of HIV-1 infection and their potential significance for HIV-1 pathogenesis and acquired immunodeficiency syndrome (AIDS). [ABSTRACT FROM AUTHOR]

This chapter is an attempt to integrate recent studies concerning the role of chemokine receptors in the initiation, development, and maintenance of allergic lung diseases collectively referred to as asthma. The pathogenesis of asthma involves the coordinated trafficking of inflammatory cells to the lungs and draining lymph nodes, as well as the activation of these inflammatory cells. Chemokine receptors and their ligands play a prominent role in directing the inflammation associated with allergic lung disease. T lymphocyte-mediated immune responses can be broadly categorized as being type 1 or type 2, based on the cell types present and the associated cytokines produced. Allergic lung disease is a predominately type 2-mediated disease. The chemokine receptors CCR4, CCR6, and CCR8 serve to promote the recruitment of type 2 T (T helper 2; Th2) cells, whereas CXCR3 antagonizes type 2 and promotes type 1 T (T helper 1; Th1) cells. The pathophysiologic manifestations of asthma, including excessive mucus production, eosinophilia, and airway hyperreactivity, are dependent upon the trafficking and activation of eosinophils, mast cells, and goblet cells. Roles for chemokine receptors, including CCR4, CCR2, and CXCR4, in the trafficking and activation of these cell types during allergic lung disease are discussed. Finally, the incidence of allergic lung disease is increasing, and the costs associated with it are substantial. Chemokine receptor expression and use by inflammatory cells during allergic lung disease makes chemokine receptors an attractive therapeutic target. Implications for drug development are discussed in the context of experimental results. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) affects 1% of the U.S. population, or 3 million people. RA is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, neovascularization, and progressive destruction of cartilage and bone. The cause(s) of RA remains poorly defined, but it is thought that both genetic and environmental factors, including molecular mimicry and host responses against cross-reactive antigens, lead to the development of autoimmune responses involving the joints. The goal of this chapter is to provide an overview of the contribution of members of the chemokine system to the immunopathogenesis of RA. This is of high clinical relevance because of the burgeoning interest in the use of chemokine and chemokine-receptor blockers in the treatment of a variety of inflammatory, autoimmune, and infectious disorders, including RA. [ABSTRACT FROM AUTHOR]

Chemokines exert multiple actions in inflammation, wound healing, and differentiation. Because these processes underlie aspects of the pathophysiology of allograft rejection, chemokine biology has been a major focus of transplantation studies. Although diverse sets of chemokines can be detected in allografts after ischemic reperfusion injury and acute and chronic rejection, recent studies now suggest that relatively few chemokine receptors play central roles in the development of transplant rejection. The antagonism of select chemokine receptors causes a reduction in leukocyte infiltration, prolongs graft function, and can synergize with other immune-suppressive regimens. Chemokine-targeted therapy may represent an important approach in the treatment of allograft rejection. [ABSTRACT FROM AUTHOR]

Chemokines regulate the process of hematopoiesis by controlling trafficking, proliferation/survival, and differentiation of hematopoietic stem and progenitor cells. Unique expression of the chemokine receptor CXCR4 in combination with adhesion molecules [very late antigen (VLA)-4, lymphocyte function-associated antigen-1 (LFA-1), and VLA-5] on early hematopoietic stem and progenitor cells makes their homing to bone marrow and seeding the stem cell niche possible. In bone marrow, the CXCL12-CXCR4 chemokine axis promotes the survival and retention of hematopoietic stem and early progenitor cells. In certain conditions, hematopoietic stem and progenitor cells are released from bone marrow to the blood circulation, a process called mobilization. Many agents that mobilize marrow progenitor cells induce or activate certain proteases of neutrophils. This leads to degradation of CXCL12 and, therefore, weakens the chemotactic activity of bone marrow. Whereas CXCL12 plays a positive role in survival and proliferation of hematopoietic stem and progenitor cells, many other chemokines suppress these processes. During their differentiation into mature cells, hematopoietic progenitor cells upregulate cell lineage-specific chemokine receptors to migrate to appropriate tissue sites. This cell type-specific switch in chemokine receptors and adhesion molecules is important for tissue-specific migration of hematopoietic cells, a process important for their differentiation or effector function in the periphery. [ABSTRACT FROM AUTHOR]

The ordered movement of lymphocytes through and positioning within lymphoid organs and peripheral sites is controlled by adhesion molecules together with chemokines and their receptors. Chemokine-mediated lymphocyte migration is critical for establishing the architecture of lymphoid organs and many aspects of lymphocyte function, including lymphocyte development, activation, and effector activity. Of the 19 chemokine receptors described in humans, all have been reported to be expressed on lymphocytes, and the expression pattern of chemokine receptors can itself be used to define and characterize lymphocyte subsets. For example, by using chemokine receptors, memory T cells can be split into distinct populations, such as central and effector memory T cells; and T helper 1 (Th1) and T helper 2 (Th2) cells exhibit distinguishable patterns of chemokine receptor expression, which can be used to study Th1/Th2 differentiation. Beyond their physiologic roles, chemokine receptors on lymphocytes are exploited by pathogens, such as in the use of CCR5 and CXCR4 by HIV-1 as coreceptors for viral entry. In this chapter, we will focus on the roles of chemokine receptors in lymphocyte trafficking in lymphoid organs and peripheral tissues and how understanding the chemokine system has shed light on larger issues in lymphocyte biology. We will discuss the roles of chemokines and chemokine receptors during the life cycles of lymphocytes—from early development through the acquisition of memory and effector functions. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC) networks dictate peripheral tolerance and immunity in lymph nodes (LNs). The type, timing, location, and interaction of LN-recruited DC subtypes are pivotal and regulated by chemokines. We propose a concept that any DC subtype including myeloid and plasmacytoid DCs (mDCs and pDCs) is fundamentally categorized by three stages depending on the function and anatomical position: naïve DC, primed DC, and effector DC. Naïve mDC precursors are recruited to inflamed tissues in response to CCR1 and CCR5 ligands to become primed mDCs, remobilized to draining LNs in response to CCR7 ligands, and activated to become effector mDCs to undergo antigen-presenting function. In contrast, pDC precursors directly migrate to LNs in a CXCR3-dependent manner. LN-recruited, primed pDCs are activated to become effector pDCs that produce large amounts of cytokines and chemokines. Concerted recruitment and adequate network formation of distinct effector DCs are pivotal to determine the type and efficacy of immune response. [ABSTRACT FROM AUTHOR]

Neutrophils are the most abundant leukocytes in circulation. They rapidly infiltrate sites of tissue injury and play a critical role in innate immune responses. In addition, they also contribute to the development of adaptive immune responses. Isolation of the human chemokine IL-8 and the cloning of its receptors CXCR1 and CXCR2, followed by the cloning of their orthologues or homologues in animals, have enabled researchers to elucidate the mechanisms of neutrophil trafficking during immune responses at a molecular level. Since then, there has been tremendous progress in understanding how the trafficking of neutrophils is regulated by the chemokine/chemokine receptor system under not only pathologic but also physiologic conditions. In this chapter, the roles of the chemokine receptors in regulating the trafficking of neutrophils are described. [ABSTRACT FROM AUTHOR]

The biochemical events that are elicited upon chemokine engagement have been a major focus of interest in many cell types responding to a plethora of different chemokines. We now appreciate that collectively, chemokines can couple to a wide range of biochemical signals including phosphoinositide lipid metabolism, elevation of intracellular calcium levels, and activation of a wide array of protein and lipid kinases as well as small GTPases. Chemokine signaling events are particularly well studied in T lymphocytes where the ordered directional migration of T lymphocytes is a key process in development, immune surveillance, and immune responses. These cells therefore offer a splendid model system in which to understand the array of signals activated by chemokines and their functional importance. One of the most robust biochemical signals elicited by chemokines is the activation of several members of the phosphoinositide 3-kinase (PI3K) family. In many cell systems, PI3Ks are known to contribute to several aspects of the migratory machinery including gradient sensing, signal amplification, actin reorganization and hence cell motility. This chapter will therefore focus on the role of PI3K-dependent signaling events in T-lymphocyte migration and points at which these events may integrate with other effectors and signaling cascades. [ABSTRACT FROM AUTHOR]

To date, all mammalian chemokine receptors and chemokine-binding proteins belong to the seven-transmembrane (7TM)-spanning family of receptors, which are typically, although not exclusively, coupled to G proteins (1). The large G protein-coupled receptor (GPCR) family comprises almost 1000 members in the human genome (2,3) accounting for in excess of 3% of transcribed sequences. This family is subdivided into the class A, B, C, and F/S families on the basis of shared motifs, and chemokine receptors specifically belong to the class A GPCR family. This review summarizes the current state of knowledge of chemokine receptor structure and discusses recent developments toward the determination of the full three-dimensional structure of these important receptors. [ABSTRACT FROM AUTHOR]

This chapter provides an overview of the literature in the field of the structural biology of chemokines. The secondary, tertiary, and quaternary structures as determined by x-ray crystallography and nuclear magnetic resonance are compared among the four chemokine families. The biological significance of chemokine structures is explored through a discussion of additional molecules that interact with the chemokines. Specific interactions of chemokines and their receptors are discussed as are interactions between chemokines and glycosaminoglycans. Additionally, a set of tables and figures summarizes the structural information available in the databases. [ABSTRACT FROM AUTHOR]

Chemokines were initially discovered in the context of inflammatory pathologies and were the curiosity of a limited number of researchers. Receptors for these cytokine molecules were identified shortly thereafter and determined to be members of the large G protein-coupled receptor (GPCR) superfamily. Collectively, these basic observations provided a framework to understand mechanisms by which leukocyte subsets could migrate into tissues in a specific manner. Nonetheless, as the field evolved, so came a realization of the broader impact of this family on diverse biological processes, which include the regulation of leukocyte trafficking in hematopoiesis, innate and adaptive immunity, angiogenesis, cancer, and viral pathogenesis. We begin this volume with an overview of research on chemokines and their receptors and then subsequently migrate into a brief discussion of key findings that defined the maturation of this field. As members of the GPCR superfamily have historically dominated drug development programs, so too has interest in chemokine receptors as therapeutic targets. [ABSTRACT FROM AUTHOR]