ReviewHistamine and astrocyte function
Graphical abstract
Introduction
Astrocytes are the most abundant non-neuronal population of cells in the central nervous system (CNS). Being assembled in highly complex networks with surrounding neurons and the cells from other germ layers (microglia, endothelial cells etc.) [1] astrocytes with heterogenous structure and function provide for fundamentals of brain homeostasis and intrinsic brain defence system [2]. During brain development, astrocytes are the central elements of neurogenesis by offering trophic support to migrating neuronal cells and guiding formation and maintenance of neural pathways, and play a role in synaptogenesis and synaptic maturation [3], [4], [5]. In the adult brain, astrocytes participate to the blood-brain barrier and blood flow control within brain [6], [7], [8]. They maintain synaptic homeostasis and intimately control the synaptic plasticity and functioning of tripartite synapse, thus regulating neuronal signalling [9], [10], [11]. Astrocytes also determine the fate of endogenous neural precursors, eliminate neurotoxins and protect neurons from oxidative damage [2], [12]. They regulate the recruitment and activity of infiltrating haematogenous cells through expression of proteases, protease inhibitors, adhesion molecules, and extracellular matrix components and contribute to the immune response in the brain through the synthesis and secretion of different cytokines and trophic factors, and thus fulfill important protective and reparative functions [2], [13], [14]. In the brain injury and/or pathological processess, astrocytes undergo morphological in physiological changes that increase their metabolic activity, needed for regenerative processes.
An intimate relationship between astrocytes and neurones appears a fundamental element of many functional interactions since by covering the majority of synapses, astrocytes are in a prime location for fostering and maintaining synaptic connectivity. A complex signalling between astrocytes and neurons on one side, and astrocytes and blood vessels on the other, enables an exchange of a huge amount of information in the CNS.
Several mechanisms have been suggested to underline the release of signalling molecules from astrocytes: reverse operation of glutamate transporters, volume-regulated anion channels, gap-junctional hemi channels, diffusional release through purinergic receptors and Ca2+-dependent exocytosis [2], [15], [16], [17], [18]. There is a wide range of receptors expressed on astrocytes that are functionally coupled to changes in membrane potential or to intracellular signalling pathways such as activation of phospholipase C or adenylate cyclase. Both pathways are associated with the changes of intracellular concentration of Ca2+ ions which allow cell-to-cell communication, typical for astrocytes. Among identified receptors such as glutamatergic, GABAergic, adrenergic, purinergic, serotonergic, muscarinic, and peptidergic receptors, which have been found on protoplasmic, fibrous, or specialized (Bergmann glia, pituicytes, Müller glia) astrocytes in situ and in vivo [13], [19]; astrocytes express also different types of histamine receptors [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]. Expression of histamine receptors enables astrocytes to be an additional neuromodulatory system that encode and integrate incoming inputs of histamine from different sources. The aim of this review is to highlight our limited understanding of the involvement of histamine and histamine receptors on astroglial cell function.
Section snippets
Histamine synthesis, metabolism and uptake
In the CNS, histamine is synthesized by decarboxylation of essential amino acid l-histidine catalysed by histidine decarboxylase (HDC) [30], [31]. HDC activity has been detected in mast cells [32] and microglia [33], [34] in addition to histaminergic neurons originating from the tuberomamillary nucleus (TMN) of the posterior hypothalamus that represent the only site of neuronal histamine synthesis in the adult mammalian brain [30], [35], [36]. In central nervous system histamine is rendered
Histamine actions in astrocytes
Several histamine actions, associated with at least three histamine receptor subtypes, expressed on astrocytes, have been identified, and are related to major astrocyte functions like ion homeostasis, energy metabolism, neurotransmitter clearance, neurotrophic activity and immune response (Fig. S1).
H1R subtype has been found connected to most of the functions, regulated by histamine (Table 2). As described later in details, activation of H1R is
Conclusions
It is quite remarkable that astrocytes support the brain through numerous functional interactions. The recent advances in our knowledge of astrocytic involvement in various neurological disorders raised further questions about their role and function in the CNS. From the evidences discussed in this review we conclude that targeting astrocytes via the three expresed receptor subtypes, histamine importantly influences the main astrocytic activities such as ion homeostasis, energy metabolism,
Acknowledgements
We would like to thank Cvetka Blažek and Jožica Košir for assistance. Financial support from the Slovenian Agency for Research (ARRS) was received through grants ARRS-P3-019, P3-067, ARRS-J3-0024, ARRS-J3-081 and ARRS-J1-2014.
References (199)
Physiology of neuronal-glial networking
Neurochem. Int.
(2010)- et al.
Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis
Cell
(2005) The mystery and magic of glia: a perspective on their roles in health and disease
Neuron
(2008)- et al.
Activation of cPLA2 and sPLA2 in astrocytes exposed to simulated ischemia in vitro
Cell Biol. Int.
(2007) - et al.
Tripartite synapses: glia the unacknowledged partner
Trends Neurosci.
(1999) - et al.
The impact of astrocytes in the clearance of neurotransmitters by uptake and inactivation
- et al.
Astrocytic neurotransmitter receptors in situ and in vivo
Prog. Neurobiol.
(1997) - et al.
Mechanisms of glutamate release from astrocytes: gap junction »hemichanneles«, purinergic receptors and exocytotic release
Neurochem. Int.
(2004) - et al.
The astrocyte odyssey
Prog. Neurobiol.
(2008) - et al.
Histamine H1-receptors mediate phosphoinositide hydrolysis in astrocyte-enriched primary cultures
Brain Res.
(1988)
Characterization of histamine H1-receptors on astrocytes in primary culture: [3H]mepyramine binding studies
Eur. J. Pharmacol.
Identification and pharmacological characterization of the histamine H3 receptor in cultured rat astrocytes
Eur. J. Pharmacol.
Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker
Brain Res.
Structural study reveals that Ser-354 determines substrate specificity on human histidine decarboxylase
J. Biol. Chem.
Histamine synthesis in the developing rat brain: evidence for a multiple compartmentation
Brain Res.
Histamine production by cultured microglial cells of the mouse
Neurosci. Lett.
The histaminergic system in the brain: structural characteristics and changes in hibernation
J. Chem. Neuroanat.
Is neurotransmitter histamine predominantly inactivated in astrocytes?
Neurosci. Lett.
Molecular and kinetic characterization of histamine transport into adult rat cultured astrocytes
Neurochem. Int.
Antibodies to the alpha q subfamily of guanine nucleotide-binding regulatory protein alpha subunits attenuate activation of phosphatidylinositol 4,5-bisphosphate hydrolysis by hormones
J. Biol. Chem.
Molecular aspects of the histamine H3 receptor
Biochem. Pharmacol.
Localization of histamine H4 receptors in the central nervous system of human and rat
Brain Res.
Autoradiographic localization of binding sites for [3H]histamine and H1- and H2-antagonists on cultured neurones and glial cells
Neuroscience
Multiple role of histamine H1-receptor-PKC-MAPK signalling pathway in histamine stimullated nerve growth factor synthesis and secretion
Biochem. Pharmacol.
Gliotransmitters travel in time and space
Neuron
Histamine H1 receptors in UC-11MG astrocytes and their regulation of cytoplasmic Ca2+
Brain Res.
Histamine stimulates glycogenolysis in human astrocytoma cells by increasing intracellular free calcium
Brain Res.
Hypothalamic neuronal histamine: implications of its homeostatic control of energy metabolism
Nutrition
Histamine regulation in glucose and lipid metabolism via histamine receptors: model for nonalcoholic steatohepatitis in mice
Am. J. Pathol.
Modulation of astrocytic glutamine synthetase expression and cell viability by histamine in cultured cortical astrocytes exposed to OGD insults
Neurosci. Lett.
Histamine up-regulates astrocytic glutamate transporter 1 and protects neurons against ischemic injury
Neuropharmacology
Activity and metabolism-related Ca2+ and mitochondrial dynamics in co-cultured human fetal cortical neurons and astrocytes
Neuroscience
Astrocytes: biology and pathology
Acta Neuropathol.
Dissection of astrocyte-mediated cues in neuronal guidance and process extensio
Glia
Calcium signal communication between glial and vascular brain cells
Acta Neurol. Belg.
Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor
Int. J. Mol. Med.
Synaptic islands defined by the territory of a single astrocyte
J. Neurosci.
Tripartite synapses: astrocytes process and control synaptic information
Trends Neurosci.
Ethanol alters the physiology of neuron-glia communication
Int. Rev. Neurobiol.
Dynamic signaling between astrocytes and neurons
Annu. Rev. Physiol.
Astrocyte control of synaptic transmission and neurovascular coupling
Physiol. Rev.
Vesicular transmitter release from astrocytes
Glia
H1-histamine receptors on human astrocytoma cells
Mol. Pharmacol.
Histamine H1-receptors on astrocytes in primary cultures: a possible target for histaminergic neurons
Agents Actions Suppl.
Molecular properties of central and peripheral histamine H1 and H2 receptors
Pflugers Arch.
Histamine H1 receptor activation stimulates mitogenesis in human astrocytoma U373 MG cells
J. Neurooncol.
Activation of histamine H1-receptor enhances neurotrophic factor secretion from cultured astrocytes
Inflamm. Res.
Involvement of histaminergic receptor mechanisms in the stimulation of NT-3 synthesis in astrocytes
Neuropharmacology
The quantum nature of drug-receptor interactions: deuteration changes binding affinities for histamine receptor ligands
PLoS One
Histamine H3 receptor in primary mouse microglia inhibits chemotaxis, phagocytosis, and cytokine secretion
Glia
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