Metabotropic glutamate (mGlu) receptors were discovered in the mid 1980s and originally described as glutamate receptors coupled to polyphosphoinositide hydrolysis. Almost 6500 articles have been published since then, and subtype-selective mGlu receptor ligands are now under clinical development for the treatment of a variety of disorders such as Fragile-X syndrome, schizophrenia, Parkinson’s disease and L-DOPA-induced dyskinesias, generalized anxiety disorder, chronic pain, and gastroesophageal reflux disorder. Prof. Erminio Costa was linked to the early times of the mGlu receptor history, when a few research groups challenged the general belief that glutamate could only activate ionotropic receptors and all metabolic responses to glutamate were secondary to calcium entry. This review moves from those nostalgic times to the most recent advances in the physiology and pharmacology of mGlu receptors, and highlights the role of individual mGlu receptor subtypes in the pathophysiology of human disorders. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.
In animals, sporadic injections of the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively damage dopaminergic neurons but do not fully reproduce the features of human Parkinson's disease. We have now developed a mouse Parkinson's disease model that is based on continuous MPTP administration with an osmotic minipump and mimics many features of the human disease. Although both sporadic and continuous MPTP administration led to severe striatal dopamine depletion and nigral cell loss, we find that only continuous administration of MPTP produced progressive behavioral changes and triggered formation of nigral inclusions immunoreactive for ubiquitin and ␣-synuclein. Moreover, only continuous MPTP infusions caused long-lasting activation of glucose uptake and inhibition of the ubiquitin-proteasome system. In mice lacking ␣-synuclein, continuous MPTP delivery still induced metabolic activation, but induction of behavioral symptoms and neuronal cell death were almost completely alleviated. Furthermore, the inhibition of the ubiquitinproteasome system and the production of inclusion bodies were reduced. These data suggest that continuous low-level exposure of mice to MPTP causes a Parkinson-like syndrome in an ␣-synucleindependent manner.neurodegeneration ͉ mitochondria ͉ neuronal inclusions ͉ Lewy bodies
We used primary cultures of cortical neurons to examine the relationship between -amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to -amyloid peptide (AP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3. DKK1 was induced at late times after AP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in AP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by -amyloid and is critically involved in the process of tau phosphorylation.
The vitamin D3 [1,25(OH) 2 D3], is a pleiotropic hormone, which regulates calcium homeostasis of the organism, induces differentiation and inhibits proliferation of various normal and cancer cells. 1 Evidence suggests different roles of vitamin D and its active metabolites in a large number of tissues. Nearly every tissue in the body has receptors for the active form of vitamin D, 1,25 dihydroxyvitamin D3 [1,25(OH) 2 D3] or calcitriol. The immunomodulatory role for 1,25(OH) 2 D3 was proposed more than 25 years ago. This latest function was essentially based on the finding that monocytes/macrophages from patients affected by the granulomatous disease sarcoidosis constitutively synthesize the active form of vitamin D3 [1,25(OH) 2 D3] from the precursor 25-hydroxyvitamin D (25OHD), as well as on the data indicating that the receptor for vitamin D (VDR) is detectable in activated, proliferating lymphocytes. 2 Nevertheless, only recently has a clearer picture of the function of 1,25(OH) 2 D3 as a determinant of immune responsiveness been obtained. The crucial role of 1,25(OH) 2 D3 in the immune system was confirmed by other evidence. First, the intracrine induction of antimicrobial activity by 1,25(OH) 2 D3 is a pivotal function of the monocyte/macrophage response to infection. Second, sub-optimal vitamin D status is a common peculiarity of many populations throughout the world, with the possible support of monocyte/macrophage metabolism of 25OHD and subsequent synthesis and action of 1,25(OH) 2 D3. 3 These observations suggested a mechanism whereby 1,25(OH) 2 D3 produced by monocytes could act upon adjacent T cells or B cells, but the consequence of such a system on normal immune regulation is still unclear. Currently, it is know that cutaneous immunity is managed by ultraviolet (UV) irradiation, which affects keratinocytes, antigen-presenting cells, such as epidermal Langerhans cells and T lymphocytes. Peripheral regulatory T cells are responsive to environmental stimuli including UV irradiation. The T-cell effector functions depend on the activation state of Langerhans cells, which can be influenced by UV irradiation. Following their encounter with exogenous antigens the epidermal Langerhans cells migrate to the skin-draining lymph nodes where they present skin-acquired antigens to naive T cells resulting in effector T-cell differentiation. Regulatory T cells induced by UV are expanded by UV-exposed cutaneous Langerhans cells. Recently, it has been shown that epidermal expression of 1,25(OH) 2 D3 connects the environment to the immune system via expansion of CD4 + CD25 +
In recent years there have been tremendous advances in our understanding of the circuitry of the basal ganglia and our ability to predict the behavioural effects of specific cellular changes in this circuit on voluntary movement. These advances, combined with a new understanding of the rich distribution and diverse physiological roles of metabotropic glutamate receptors in the basal ganglia, indicate that these receptors might have a key role in motor control and raise the exciting possibility that they might provide therapeutic targets for the treatment of Parkinson's disease and related disorders.
Aggregates of beta-amyloid peptide (betaAP), the main constituent of amyloid plaques in Alzheimer's brain, kill neurons by a not yet defined mechanism, leading to apoptotic death. Here, we report that both full-length betaAP((1-40)) or ((1-42)) and its active fragment betaAP((25-35)) act as proliferative signals for differentiated cortical neurons, driving them into the cell cycle. The cycle followed some of the steps observed in proliferating cells, including induction of cyclin D1, phosphorylation of retinoblastoma, and induction of cyclin E and A, but did not progress beyond S phase. Inactivation of cyclin-dependent protein kinase-4 or -2 prevented both the entry into S phase and the development of apoptosis in betaAP((25-35))-treated neurons. We conclude that neurons must cross the G1/S transition before succumbing to betaAP signaling, and therefore multiple steps within this pathway may be targets for neuroprotective agents.-Copani, A., Condorelli, F., Caruso, A., Vancheri, C., Sala, A., Giuffrida Stella, A. M., Canonico, P. L., Nicoletti, F., Sortino, M. A. Mitotic signaling by beta-amyloid causes neuronal death.
Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.BDNF | histone acetylation | MDD | glutamatergic neurotransmission | chromatin
Almost 25 years after the first report that glutamate can activate receptors coupled to heterotrimeric G-proteins, tremendous progress has been made in the field of metabotropic glutamate receptors. Now, eight members of this family of glutamate receptors, encoded by eight different genes that share distinctive structural features have been identified. The first cloned receptor, the metabotropic glutamate ( mGlu) receptor mGlu1 has probably been the most extensively studied mGlu receptor, and in many respects it represents a prototypical subtype for this family of receptors. Its biochemical, anatomical, physiological, and pharmacological characteristics have been intensely investigated. Together with subtype 5, mGlu1 receptors constitute a subgroup of receptors that couple to phospholipase C and mobilize Ca(2+) from intracellular stores. Several alternatively spliced variants of mGlu1 receptors, which differ primarily in the length of their C-terminal domain and anatomical localization, have been reported. Use of a number of genetic approaches and the recent development of selective antagonists have provided a means for clarifying the role played by this receptor in a number of neuronal systems. In this article we discuss recent advancements in the pharmacology and concepts about the intracellular transduction and pathophysiological role of mGlu1 receptors and review earlier data in view of these novel findings. The impact that this new and better understanding of the specific role of these receptors may have on novel treatment strategies for a variety of neurological and psychiatric disorders is considered
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