CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 9, Issue 5, 2010

Vitamin D Links Genetic and Environmental Risk Factors in Multiple Sclerosis The risk to develop multiple sclerosis (MS) is well known to be co-defined by genetic and environmental factors. Possession of the major histocompatibility complex (MHC) allele HLA-DRB1*1501 represents by far the strongest genetic risk factor, while much smaller contributions are made by a range of other genes. Still, even this HLA-DRB1*1501 gene explains only a small part of the MS risk. Environmental factors are also relevant to the MS risk, and these factors notably include vitamin D levels, which are influenced both by diet and sunlight exposure. Low levels of vitamin D increase the MS risk. It now emerges that vitamin D levels and MHC are more intimately linked that previously appreciated. Not only does this start to explain much more of the MS risk, it also brings new life to the idea of using vitamin D as a therapeutic compound in MS. Epidemiological evidence for an effect of sunlight and vitamin D levels on the MS risk has been accumulating for many years. The geographical distribution of MS, being more prevalent in less sunny areas, is consistent with a protective effect of sunlight-induced vitamin D. Migrant studies tell the same tale. The more recently established effect of birth month points in the same direction. In the northern hemisphere people born in spring have a somewhat higher risk to develop MS than people born in autumn. Seasonal fluctuations in maternal levels of vitamin D during pregnancy could well account for this bias. Direct assessment of serum levels of vitamin D in relapsing-remitting MS patients confirms that they are generally lower than in healthy control subjects, with the most prominent difference occurring at the time of a clinical relapse. These apparently protective effects of vitamin D may in part relate to its anti-inflammatory effects. In animal models of neuroinflammation, vitamin D mitigates clinical disease. In cell culture models, it stimulates production of the anti-inflammatory mediator interleukin-10, and the development of regulatory T cells which control autoimmune responses. This even appears to be a self-amplifying effect, since vitamin D promotes expression of the vitamin D receptor itself. Now, as it turns out, vitamin D also influences the expression of HLA-DRB1*15, the major genetic risk factor in MS. While it remains to be established what exactly the mechanisms might be by which altered expression of the HLA-DRB1*1501 haplotype exerts an effect on the development of MS, the mere fact that its expression is linked to vitamin D levels uncovers a critical link between environmental factors and genetic risk factors. Such a link may well explain the somewhat confusing data that have accumulated on the MS risks in twins. While the concordance rate of MS among identical twins in Canada is close to 30%, it is only around 14% in Italy. Not only has it remained puzzling why these twin data would be so different in different geographical areas, it has also remained obscure why concordance rates between identical twins are so much higher than between non-identical twins, or other family members for that matter. The idea that co-operative effects by multiple genes would account for this has not found support from genome-wide association studies, which have revealed only very weak genetic effects by any other gene than HLA-DRB1*1501. A co-operative effect between this gene and maternal vitamin D levels during pregnancy and the first years of life, on the other hand, now becomes a more attractive explanation. After all, identical twins share this factor, while non-identical twins do not. The effects of vitamin D, and its link with the genetic MS risk, clearly raise the question whether or not vitamin D could be used as a therapeutic compound to control MS, or even more intriguing, to prevent it. Studies of vitamin D levels in young children have suggested that in the years before MS starts to become apparent, vitamin D levels are markedly lower in those children that go on to develop MS. Along with the month-of-birth effect, this makes a strong case to stimulate anyone to maintain healthy levels of vitamin D, especially early in life. This may not just help reduce the incidence of MS, but of other disorders as well. The question whether vitamin D can be used to slow down MS once it has already started, is another. Some evidence suggests that it might, and the option to do so is too attractive to ignore. Yet, high levels of vitamin D pose well-known risks to calcium metabolism. Caution is therefore required in exploring the use of high doses of vitamin D as a disease-modifying strategy in MS. More is not always better. At this point in time, however, all the evidence argues in favor of at least trying.

Heptahelical G protein-coupled receptors (GPCR) constitute one of the most studied groups of proteins in the genome. Intense investigation of this protein superfamily is more than justified as therapeutics targeting the GPCR superfamily account for nearly half of the current pharmacopeia. Along with many years of exemplary scientific research into the activity of GPCRs has come the creeping concept of diminishing novel scientific returns based on this research, an oft-quoted phrase among GPCR molecular biologists represents this, i.e., ‘is there anything else we can learn?’ As with all such dogmatic and pessimistic statements the answer is a resounding no. It seems that the more we understand and appreciate the importance of GPCRs in both physiology and pharmacology, the more we realize in essence how little we know of their true, in vivo, nature. Our current generation of GPCR biologists are now tackling this important issue, as they start to step away from more artificial recombinant systems in attempting to understand and investigate GPCR biology in true physiological settings. One of the most important aspects of extending our appreciation of physiological GPCR activity is the cellular or tissue context that the receptor is expressed in. This is nowhere more important than in the central nervous system (CNS) as multiple, highly polarized, cell types and tissues are in a much smaller area than most peripheral tissues. In this special issue we have attempted to look to the future of GPCR research and investigation in this important growth area. We shall explore the huge potential of targeting multiple diverse CNS GPCR systems as well as how our understanding of the true in situ nature of GPCRs in the CNS, at the modulatory and protein-protein interaction level, will greatly assist our development of future neurotherapeutics. Exploring the possibilities of the complex CNS GPCR environment has allowed us to appreciate the presence of novel receptor system therapeutic targets such as those for: vasoactive intestinal peptide (White et al.), metabotropic glutamatergics (Ribeiro et al.), gonadotropin-releasing hormone (Wang et al.), cannabinoids (Bisogno & Di Marzo), tachykinins (Pantaleo et al.), dopamine (Cadet et al.), and Ghrelin (Cong et al.). The rational targeting of these important CNS systems has the potential to treat conditions as varied as neurodegeneration, aging, stress resistance, and the neurological impacts of metabolic syndromes. In addition to appreciating how we can therapeutically target important diverse GPCR systems in the CNS, in this special issue we have also addressed important issues related to connecting our molecular understanding of how GPCRs truly function in complex and diverse cellular environments. To this end we present in-depth studies into the physiological and pharmacological importance of receptor hetereomerization of GPCRs in the CNS (Albizu et al.; Ferre et al.) as well as the importance of how multiple neuronal receptor modulatory and trafficking processes can affect GPCR-based neurophysiological activities (Lopez-Gimenez & Milligan; Lopez de Maturana & Sanchez-Pernaute, Bunnett & Cottrell). With respect to this most important of therapeutic targets in the CNS it seems that with further research we may exponentially uncover yet more and more detail of the workings of this protein superfamily.

Dopamine (DA), the most abundant catecholamine in the basal ganglia, participates in the regulation of motor functions and of cognitive processes such as learning and memory. Abnormalities in dopaminergic systems are thought to be the bases for some neuropsychiatric disorders including addiction, Parkinson's disease, and Schizophrenia. DA exerts its arrays of functions via stimulation of D1-like (D1 and D5) and D2-like (D2, D3, and D4) DA receptors which are located in various regions of the brain. The DA D1 and D2 receptors are very abundant in the basal ganglia where they exert their functions within separate neuronal cell types. The present paper focuses on a review of the effects of stimulation of DA D1 receptors on diverse signal transduction pathways and gene expression patterns in the brain. We also discuss the possible involvement of the DA D1 receptors in DA-mediated toxic effects observed both in vitro and in vivo. Future studies using more selective agonist and antagonist agents and the use of genetically modified animals should help to further clarify the role of these receptors in the normal physiology and in pathological events that involve DA.

G protein-coupled receptors (GPCRs) are expressed throughout the nervous system where they regulate multiple physiological processes, participate in neurological diseases, and are major targets for therapy. Given that many GPCRs respond to neurotransmitters and hormones that are present in the extracellular fluid and which do not readily cross the plasma membrane, receptor trafficking to and from the plasma membrane is a critically important determinant of cellular responsiveness. Moreover, trafficking of GPCRs throughout the endosomal system can initiate signaling events that are mechanistically and functionally distinct from those operating at the plasma membrane. This review discusses recent advances in the relationship between signaling and trafficking of GPCRs in the nervous system. It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to drug development.

The neuroendocrine hormone ghrelin is an octanoylated 28-residue peptide that exerts numerous physiological functions. Ghrelin exerts its effects on the body mainly through a highly conserved G protein-coupled receptor known as the growth hormone secretagagogue receptor subtype 1a (GHS-R1a). Ghrelin and GSH-R1a are widely expressed in both peripheral and central tissues/organs, and ghrelin signaling plays a critical role in maintaining energy balance and neuronal health. The multiple orexigenic effects of ghrelin and its receptor have been studied in great detail, and GHS-R1a-mediated ghrelin signaling has long been a promising target for the treatment of metabolic disorders, such as obesity. In addition to its well-characterized metabolic effects, there is also mounting evidence that ghrelin-mediated GHS-R1a signaling exerts neuroprotective effects on the brain. In this review, we will summarize some of the effects of ghrelin-mediated GSH-R1a signaling on peripheral energy balance and cognitive function. We will also discuss the potential pharmacotherapeutic role of GSH-R1a-mediated ghrelin signaling for the treatment of complex neuroendocrine disorders.

The G-protein coupled receptors for Δ9-tetrahydrocannabinol, the major psychoactive principle of marijuana, are known as cannabinoid receptors of type 1 (CB1) and 2 (CB2) and play important functions in degenerative and inflammatory disorders of the central nervous system. Whilst CB1 receptors are mostly expressed in neurons, where they regulate neurotransmitter release and synaptic strength, CB2 receptors are found mostly in glial cells and microglia, which become activated and over-express these receptors during disorders such as Alzheimer's disease, multiple sclerosis, amyotropic lateral sclerosis, Parkinson's disease, and Huntington's chorea. The neuromodulatory actions at CB1 receptors by endogenous agonists (‘endocannabinoids’), of which anandamide and 2- arachidonoylglycerol are the two most studied representatives, allows them to counteract the neurochemical unbalances arising during these disorders. In contrast, the immunomodulatory effects of these lipophilic mediators at CB2 receptors regulate the activity and function of glia and microglia. Indeed, the level of expression of CB1 and CB2 receptors or of enzymes controlling endocannabinoid levels, and hence the concentrations of endocannabinoids, undergo time- and brain region-specific changes during neurodegenerative and neuroinflammatory disorders, with the initial attempt to counteract excitotoxicity and inflammation. Here we discuss this plasticity of the endocannabinoid system during the aforementioned central nervous system disorders, as well as its dysregulation, both of which have opened the way to the use of either direct and indirect activators or blockers of CB1 and CB2 receptors for the treatment of the symptoms or progression of these diseases.

Stimulation of Group I metabotropic glutamate receptors (mGluR1 and mGluR5) leads to activation of a wide variety of signalling pathways. mGluRs couple to Gαq/11 proteins, activating phospholipase Cβ1 resulting in both diacylglycerol and inositol-1,4,5- triphosphate formation followed by the activation of protein kinase C. In addition, mGluR activation can lead to modulation of a number of ion channels, such as different types of calcium and potassium channels. Group I mGluRs can also activate other downstream protein kinases, such as ERK1/2 and AKT, which are implicated in cellular growth, differentiation, and survival. Moreover, Group I mGluRs interact with a variety of different proteins that are important for the regulation of synaptic signalling, such as Homer and PDZ domain containing proteins, such as Tamalin. A role for mGluR1/5 in a number of disease states has also been proposed. As mGluR1/5 signal transduction is complex and involves multiple partners, a better understanding of alterations in mGluR signalling in brain disorders will be required in order to discern the molecular and cellular basis of these pathologies. This review will highlight recent findings concerning mGluR signaling alterations in brain pathologies, such as stroke, fragile X syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and drug addiction.

A number of G-protein-coupled receptors (GPCRs) are currently under consideration as potential therapeutic targets for drugs acting in the central nervous system (CNS). Attempts to discover new medications have operated under the assumption that GPCRs are monomers and that a specific drug activates one single receptor coupled to one single signal transduction mechanism. In the neuronal membrane, GPCRs are now known to be arranged into homo- and hetero-oligomers; drugs acting on a single receptor within a specific heteromer context are thought to induce a particular downstream signaling. However, there is recent evidence showing that heteromertailored drugs can be designed that display different affinities for a given receptor depending on the receptor partners contained within the heteromer. It can therefore be predicted that customized drugs targeting a specific receptor heteromer in the CNS might imporove safety and efficacy for their therapeutic targets. Finally, it will be important to identify receptor heteromers that are involved in the pathogenesis of diseases, such as the recently discovered dopamine D1-D3 receptor heteromer, which might play a key role in L-DOPA-induced dyskinesia in Parkinson's disease.

Dopamine modulation of excitatory neurotransmission is critical in the control of movement, emotion and reward. In the striatum, medium size spiny neurons (MSNs) are responsible for the integration of cortical and thalamic information that flows through parallel, partly overlapping, loops and determines adequate experience-dependent responses. Dopamine acts on MSNs through two sets of G protein-coupled receptors (GPCRs), the D1-like and D2-like receptors, which can have opposing or synergistic downstream effects. Notably, these two types of striatal dopamine receptors are segregated into the striatonigral (direct) and striatopallidal (indirect) projecting neurons. Thus, dopamine receptor expression determines the morphological and functional neuronal phenotype of MSNs. Moreover, dopamine regulates glutamatergic corticostriatal transmission, critically controlling the induction of long-term potentiation and long-term depression at these synapses, regulating striatal synaptic plasticity. In addition to dopamine receptors, the induction and expression of plasticity mechanisms is regulated by other GPCRs, most importantly adenosine A2A receptors, metabotropic glutamate mGluR5 receptors and endocannabinoid CB1 receptors. This review focuses on synaptic modulation and plasticity on excitatory corticostriatal synapses by GPCRs.

Internalisation of the mu opioid receptor from the surface of cells is generally achieved by receptor occupancy with agonist ligands of high efficacy. However, in many situations the potent analgesic morphine fails to promote internalisation effectively and whether there is a direct link between this and the propensity for the sustained use of morphine to result in both tolerance and dependence has been studied intensely. Although frequently described as a partial agonist, this characteristic appears insufficient to explain the poor capacity of morphine to promote internalisation of the mu opioid receptor. Experiments performed using both transfected cell systems and ex vivo/in vivo models have provided evidence that when morphine can promote internalisation of the mu receptor there is a decrease in the development of tolerance and dependence. Although aspects of this model are controversial, such observations suggest a number of approaches to further enhance the use of morphine as an analgesic.

Our understanding of the complex signaling neurophysiology of the central nervous system has facilitated the exploration of potential novel receptor-ligand system targets for disorders of this most complex organ. In recent years, many relatively neglected receptor-ligand systems have been re-evaluated with respect to their ability to potently modulate discrete tracts in the central nervous system. One such system is the tachykinin (previously neurokinin) system. The multiple heptahelical G protein-coupled receptors and neuropeptide ligands that comprise this system may be significantly involved in more central nervous systems actions than previously thought, including sleep disorders, amyotrophic lateral sclerosis, Alzheimer's disease and Machado-Joseph disease. The development of our understanding of the role of the tachykinin receptor-ligand system in higher order central functions is likely to allow the creation of more specific and selective tachykinin-related neurotherapeutics.

Because G protein-coupled receptors (GPCRs) are numerous, widely expressed and involved in major physiological responses, they represent a relevant therapeutic target for drug discovery, particularly regarding pharmacological treatments of neurological disorders. Among the biological phenomena regulating receptor function, GPCR heteromerization is an important emerging area of interest and investigation. There is increasing evidence showing that heteromerization contributes to the pharmacological heterogeneity of GPCRs by modulating receptor ontogeny, activation and recycling. Although in many cases the physiological relevance of receptor heteromerization has not been fully established, the unique pharmacological and functional properties of heteromers are likely to lead to new strategies in clinical medicine. This review describes the main GPCR heteromers and their implications for major neurological disorders such as Parkinson's disease, schizophrenia and addiction. A better understanding of molecular mechanisms underlying drug interactions related to the targeting of receptor heteromers could provide more specific and efficient therapeutic agents for the treatment of brain diseases.

Receptors for hormones of the hypothalamic-pituitary-gonadal axis are expressed throughout the brain. Age-related decline in gonadal reproductive hormones cause imbalances of this axis and many hormones in this axis have been functionally linked to neurodegenerative pathophysiology. Gonadotropin-releasing hormone (GnRH) plays a vital role in both central and peripheral reproductive regulation. GnRH has historically been known as a pituitary hormone; however, in the past few years, interest has been raised in GnRH actions at non-pituitary peripheral targets. GnRH ligands and receptors are found throughout the brain where they may act to control multiple higher functions such as learning and memory function and feeding behavior. The actions of GnRH in mammals are mediated by the activation of a unique rhodopsin-like G protein-coupled receptor that does not possess a cytoplasmic carboxyl terminal sequence. Activation of this receptor appears to mediate a wide variety of signaling mechanisms that show diversity in different tissues. Epidemiological support for a role of GnRH in central functions is evidenced by a reduction in neurodegenerative disease after GnRH agonist therapy. It has previously been considered that these effects were not via direct GnRH action in the brain, however recent data has pointed to a direct central action of these ligands outside the pituitary. We have therefore summarized the evidence supporting a central direct role of GnRH ligands and receptors in controlling central nervous physiology and pathophysiology.

Vasoactive intestinal peptide (VIP) is a basic 28 amino acid peptide that binds to a member of the class II family of G proteincoupled receptors (GPCRs). It is widely expressed throughout the body and plays an important role in numerous biological functions. VIP acts via three different GPCRs: VPAC1, VPAC2, and PAC1, which have been identified in various tissues, including brain, lung, kidney, gastrointestinal tract, tongue, and also on immunocompetent cells such as macrophages and lymphocytes. There is mounting evidence that VIP expression and signaling is altered in numerous neurological disorders, and it is becoming apparent that VIP and its receptors could be therapeutic loci for the treatment of several pathological conditions of the central nervous system. In this review, we describe the pathology of several major neurological disorders and discuss the potential pharmacotherapeutic role of VIP and its receptors for the treatment of disorders such as Alzheimer's disease, Parkinson's disease, and Autism Spectrum Disorders.