Pathophysiology of astroglial purinergic signalling

Abstract

Astrocytes are fundamental for central nervous system (CNS) physiology and are the fulcrum of neurological diseases. Astroglial cells control development of the nervous system, regulate synaptogenesis, maturation, maintenance and plasticity of synapses and are central for nervous system homeostasis. Astroglial reactions determine progression and outcome of many neuropathologies and are critical for regeneration and remodelling of neural circuits following trauma, stroke, ischaemia or neurodegenerative disorders. They secrete multiple neurotransmitters and neurohormones to communicate with neurones, microglia and the vascular walls of capillaries. Signalling through release of ATP is the most widespread mean of communication between astrocytes and other types of neural cells. ATP serves as a fast excitatory neurotransmitter and has pronounced long-term (trophic) roles in cell proliferation, growth, and development. During pathology, ATP is released from damaged cells and acts both as a cytotoxic factor and a proinflammatory mediator, being a universal "danger" signal. In this review, we summarise contemporary knowledge on the role of purinergic receptors (P2Rs) in a variety of diseases in relation to changes of astrocytic functions and nucleotide signalling. We have focussed on the role of the ionotropic P2X and metabotropic P2YRs working alone or in concert to modify the release of neurotransmitters, to activate signalling cascades and to change the expression levels of ion channels and protein kinases. All these effects are of great importance for the initiation, progression and maintenance of astrogliosis-the conserved and ubiquitous glial defensive reaction to CNS pathologies. We highlighted specific aspects of reactive astrogliosis, especially with respect to the involvement of the P2X 7 and P2Y 1 R subtypes. Reactive astrogliosis exerts both beneficial and detrimental effects in a context-specific manner determined by distinct molecular signalling cascades. Understanding the role of purinergic signalling in astrocytes is critical to identifying new therapeutic principles to treat acute and chronic neurological diseases.

Supportive or detrimental roles of P2Y receptors in brain pathology?—The two faces of P2Y receptors in stroke and neurodegeneration detected in neural cell and in animal model studies

“…It has been described that increased intracellular Ca 2+ in astrocytes leads to release of proinflammatory cytokines, glutamate, and ATP that exacerbates the release by further stimulation of intracellular Ca 2+ rise [81][82][83][84][85][86]. Especially under pathological conditions, this contributes to cellular damage, as can be seen in the model systems.…”

Alcohol Abrogates Intracellular Ca2+ Elevation by Angiotensin II and ATP in Cultured Rat Astrocytes

“…The spatial and temporal differences in Ca 2+ mobilization in the same cell demonstrate the diversity in the regulation of [Ca 2+ ]i even though activation of AT1 receptor by Ang II and P2Y receptor by ATP both are coupled to Gq-PLC-IP3 signaling transduction pathway [2,4]. What is/are the underlying mechanism(s) for these differences are not clear and it is worth to be elucidated in future studies.…”

“…Astrocytes have a robust and dynamic intracellular Ca 2+ activity in response to stimulation by various neurotransmitters and neuromodulators such as angiotensin II, glutamate, and ATP [1][2][3][4]. ATP evokes Ca 2+ bursts in astrocytes by activation of purinergic receptors [4] and angiotensin II (AngII) by stimulation of AT1 receptors [2].…”

“…ATP evokes Ca 2+ bursts in astrocytes by activation of purinergic receptors [4] and angiotensin II (AngII) by stimulation of AT1 receptors [2]. Intracellular Ca 2+ mobilization by the peptide and high energy purine signaling molecules enhances astrocyte cycling excitatory neurotransmitter glutamate, which governs the social behavior and cognitive ability [5][6][7].…”

P2X7 receptors and Fyn kinase mediate ATP-induced oligodendrocyte progenitor cell migration

“…Extracellular ATP can activate P2 receptors, which include ligand-gated ion channel receptors (P2X receptors) and metabotropic receptors (P2Y receptors) [15]. P2X receptors are ATP-gated ion channels, mediating intracellular potassium efflux, and extracellular sodium and calcium ions influx [16].…”