Purinergic signalling

About: Purinergic signalling is a research topic. Over the lifetime, 4278 publications have been published within this topic receiving 210070 citations. The topic is also known as: purinergic signaling.

Receptors for Purines and Pyrimidines

Abstract: ### A. Overview Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface receptors termed purine receptors. In this review particular emphasis is placed on the discrepancy between the

International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors

Abstract: Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A(1), A(2A), A(2B), and A(3). The A(2A) and A(2B) receptors preferably interact with members of the G(s) family of G proteins and the A(1) and A(3) receptors with G(i/o) proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A(3) receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are pharmacological tools that can be used to classify A(1), A(2A), and A(3) receptors but few drugs that interact selectively with A(2B) receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homology-based modelling. Both agonists and antagonists are being developed as potential drugs.

Nomenclature and classification of purinoceptors

Abstract: “Receptors recognize a distinct chemical entity and translate information from that entity into a form that the cell can read to alter its state” (Kenakin et al., 1992). Even though the receptors are often pharmacologically defined on the basis of synthetic compounds, they are assumed to have developed to respond to endogenous molecules. Therefore, receptors are generally named on the basis of their natural ligands. Hence, it is appropriate to very briefly summarize the evidence that purine nucleotides and nucleosides are natural ligands for a wide class of receptors. In a seminal paper, Drury and Szent-Gyorgyi (1929) showed that adenosine exerted a large number of biological effects, including bradycardia and vasodilation. A wider interest in the role of adenosine followed from the demonstration in 1963 that adenosine can be produced by the hypoxic heart. Two groups independently formulated the hypothesis that adenosine may be involved in the metabolic regulation of coronary blood flow (Berne, 1963; Gerlach et al., 1963). The observation by de Gubareff and Sleator (1965) that the actions of adenosine in heart tissue could be blocked by caffeine suggested the existence of an adenosine receptor. The potent cardiovascular effects of adenosine led to an interest in the synthesis of new adenosine analogs, and careful dose-response studies with a number of these drugs (Cobbin et al., 1974) strongly suggested the presence of a receptor for adenosine-like compounds. Sattin and Rall (1970) reported that adenosine increased cyclic AMP accumulation in slices of rodent brain and that this adenosine-induced second-messenger response was blocked by methylxanthines. Their findings suggested that adenosine receptors exist in the central nervous system. The essentially simultaneous findings by Mcilwain (1972), that such brain slices actually elaborate adenosine in concentrations that would be sufficient to elevate cyclic AMP, provided support that these putative receptors were physiologically occupied by adenosine. Thus, in the 1970s there was good evidence that there were receptors for adenosine at which methylxanthines acted as antagonists. Biochemical evidence for the existence of multiple adenosine receptors was subsequently provided by the demonstration that adenosine analogs increased cyclic AMP production in some preparations and decreased it in others. Because the relative agonist potency for a variety of adenosine analogs was different for these two types of effects, the presence of two classes of receptors, called A1 and A2 (van Calker et al., 1979) or Ri and Ra (Londos et al., 1980), was proposed. The A1/A2 nomenclature is now generally used. The presence of receptors for ADP, particularly on blood platelets, was also recognized several decades ago. Studies of the factors in blood that induce platelet aggregation led to the identification of ADP as an active component present in red blood cell extracts (Gaarder et al., 1961). The evidence that ADP and adenosine (presumably A2) receptors exist on platelets was summarized by Haslam and Cusack (1981). Four decades ago, ATP was shown to produce important cardiovascular effects (Green and Stoner, 1950) and to be released from sensory nerves (Holton and Holton, 1954; Holton, 1959), hinting at a role in neural transmission. In his landmark review of purinergic nerves, Burnstock (1972) postulated the existence of specific ATP receptors. Although evidence in support of this idea was not overwhelming at the time, many subsequent studies have supported the existence of receptors for extracellular ATP (Burnstock and Brown, 1981; Gordon, 1986; O’Connor et al., 1991). Similarly, the evidence is now compelling that ATP plays important physiological and/ or pathophysiological roles in a variety of biological systems, including that of a neurotransmitter in peripheral and central neurons. Finally, diadenosinetetraphosphate is a dinucleotide stored in synaptic vesicles and chromaffin granules (Flodgaard and Klenow, 1982; Rodriguez del Castillo et al., 1988) and released therefrom (Pintor et al., 1991a, 1992). The purine dinucleotide also binds with subnanomolar affinity to receptors (Pintor et al., 1991b, 1993) and exerts biological effects (Pintor et al., 1993), indicating that it is an endogenous purinoceptor ligand. Thus, strong evidence for the presence of receptors for the endogenous ligands adenosine, ADP, ATP, and dia-denosinetetraphosphate had accumulated. This group of receptors is called the purinoceptors. If at some future time there is compelling evidence that UTP, or another pyrimidine nucleotide, is an endogenous ligand at receptors that respond poorly or not at all to ATP, then this terminology may need revision.

The Role and Regulation of Adenosine in the Central Nervous System

Abstract: Adenosine is a modulator that has a pervasive and generally inhibitory effect on neuronal activity. Tonic activation of adenosine receptors by adenosine that is normally present in the extracellular space in brain tissue leads to inhibitory effects that appear to be mediated by both adenosine A1 and A2A receptors. Relief from this tonic inhibition by receptor antagonists such as caffeine accounts for the excitatory actions of these agents. Characterization of the effects of adenosine receptor agonists and antagonists has led to numerous hypotheses concerning the role of this nucleoside. Previous work has established a role for adenosine in a diverse array of neural phenomena, which include regulation of sleep and the level of arousal, neuroprotection, regulation of seizure susceptibility, locomotor effects, analgesia, mediation of the effects of ethanol, and chronic drug use.

Physiology and Pathophysiology of Purinergic Neurotransmission

Abstract: This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.