### 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

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Receptors for Purines and Pyrimidines

P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP. Seven genes in vertebrates encode P2X receptor subunits, which are 40–50% identical in amino acid ...

Molecular Physiology of P2X Receptors

Commercial polychlorinated biphenyls (PCBs) and environmental extracts contain complex mixtures of congeners that can be unequivocally identified and quantitated. Some PCB mixtures elicit a spectrum of biochemical and toxic responses in humans and laboratory animals and many of these effects resemble those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons, which act through the aryl hydrocarbon (Ah)-receptor signal transduction pathway. Structure-activity relationships developed for PCB congeners and metabolites have demonstrated that several structural classes of compounds exhibit diverse biochemical and toxic responses. Structure-toxicity studies suggest that the coplanar PCBs, namely, 3,3',4,4'-tetrachlorobiphenyl (tetraCB), 3,3',4,4',5-pentaCB, 3,3',4,4',5,5'-hexaCB, and their monoortho analogs are Ah-receptor agonists and contribute significantly to the toxicity of the PCB mixtures. Previous studies with TCDD and structurally related compounds ...

Polychlorinated Biphenyls (PCBs): Environmental Impact, Biochemical and Toxic Responses, and Implications for Risk Assessment

“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.

https://pharmrev.aspetjournals.org/content/pharmrev/46/2/143.full.pdf

Nomenclature and classification of purinoceptors

Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy.

1. ATP-activated inward current in PC12 pheochromocytoma cells was characterized using the whole-cell voltage-clamp technique. 2. ATP (100 microM) applied extracellular elicited an inward rectifying current with a reversal potential of about +7 mV. The current was desensitized in seconds in spite of continued presence of ATP. 3. A comparison was made of the ability of ATP and its analogues. The order of potency in activating the inward current was ATP greater than ATP gamma S greater than ADP; AMP, adenosine and alpha, beta-methylene ATP were inactive at concentrations up to mM. 4. The ATP-activated current was also observed when external Na+ and Ca2+ were replaced with K+, TEA, Tris or glucosamine. The order of ion selectivity was Na+ greater than K+ greater than TEA not equal to Tris greater than glucosamine. 5. The ATP-activated current was also recorded in extracellular solutions containing Ca2+ as the only external cation. The amplitude increased as the concentration of Ca2+ was increased in the range between 1.8 and 16.2 mM. However, the current amplitude decreased at higher Ca2+ concentrations and the current was not recorded in 110 mM-Ca2+ solution. 6. In the presence of 140 mM-Na+ in the external solution, the current amplitude also decreased as the external Ca2+ concentration was increased (from 1.8 to 16.2 mM). 7. The results indicate that Ca2+ as well as monovalent cations permeate through the ATP-sensitive pathway and that Ca2+ blocks ion permeation, including its own permeation through the pathway. This regulation by extracellular Ca2+ is different to the ATP-activated current in smooth muscle cells.

An ATP-activated conductance in pheochromocytoma cells and its suppression by extracellular calcium.

Extracellular adenosine 5'-triphosphate-evoked glutamate release in cultured hippocampal neurons.

Metabolism of drugs in old rats. I. Activities of NADPH-linked electron transport and drug-metabolizing enzyme systems in liver microsomes of old rats.

Akira Takanaka

Papers

An ATP-activated conductance in pheochromocytoma cells and its suppression by extracellular calcium.

Extracellular adenosine 5'-triphosphate-evoked glutamate release in cultured hippocampal neurons.

Metabolism of drugs in old rats. I. Activities of NADPH-linked electron transport and drug-metabolizing enzyme systems in liver microsomes of old rats.

Metabolism of drugs in old rats (ii) metabolism in vivo and effect of drugs in old rats

Extracellular adenosine 5′-triphosphate-evoked norepinephrine secretion not relating to voltage-gated Ca channels in pheochromocytoma PC12 cells