Purinergic signalling

Purinergic signalling (or signaling: see American and British English differences) is a form of extracellular signalling mediated by purine nucleotides and nucleosides such as adenosine and ATP. It involves the activation of purinergic receptors in the cell and/or in nearby cells, thereby regulating cellular functions. It was proposed after Adenosine triphosphate (ATP) was identified in 1970 as the transmitter responsible for non-adrenergic, non-cholinergic neurotransmission. Nowadays, it is known that ATP acts as a co-transmitter in most, if not all, nerves in the central and peripheral nervous system. Receptors for adenosine (called P1) and for ATP and ADP (called P2) were distinguished in 1978. Later, the P2 receptors were subdivided into P2X and P2Y families based on their different mechanisms. In the early 1990s, when the receptors to purines and pyrimidines were cloned and characterized, numerous subtypes of P1 and P2 receptors were discovered. The purinergic signalling complex of a cell is sometimes referred to as the "purinome".

Background

Evolutionary origins

Purinergic receptors, represented by several families, are among the most abundant receptors in living organisms and appeared early in evolution. Among invertebrates, the purinergic signalling system has been found in bacteria, amoeba, ciliates, algae, fungi, sea anemones, ctenophores, platyhelminthes, nematodes, crustacea, molluscs, annelids, echinoderms, and insects. In green plants, extracellular ATP and other nucleotides induce an increase in the cytosolic concentration of calcium ions, in addition to other downstream changes that influence plant growth and modulate responses to stimuli. In 2014, the first purinergic receptor in plants, DORN1, was discovered. The primitive P2X receptors of unicellular organisms often share low sequence similarity with those in mammals, yet they still retain micromolar sensitivity to ATP. The evolution of this receptor class is estimated to have occurred over a billion years ago.

Molecular mechanisms Generally speaking, all cells have the ability to release nucleotides. In neuronal and neuroendocrinal cells, this mostly occurs via regulated exocytosis. Released nucleotides can be hydrolyzed extracellularly by a variety of cell surface-located enzymes referred to as ectonucleotidases. The purinergic signalling system consists of transporters, enzymes and receptors responsible for the synthesis, release, action, and extracellular inactivation of (primarily) ATP and its extracellular breakdown product adenosine. The signalling effects of uridine triphosphate (UTP) and uridine diphosphate (UDP) are generally comparable to those of ATP.

Purinergic receptors

Purinergic receptors are specific classes of membrane receptors that mediate various physiological functions such as the relaxation of gut smooth muscle, as a response to the release of ATP or adenosine. There are three known distinct classes of purinergic receptors, known as P1, P2X, and P2Y receptors. Cell signalling events initiated by P1 and P2Y receptors have opposing effects in biological systems.

Nucleoside transporters Nucleoside transporters (NTs) are a group of membrane transport proteins which transport nucleoside substrates including adenosine across the membranes of cells and/or vesicles. NTs are considered to be evolutionarily ancient membrane proteins and are found in many different forms of life. There are two types of NTs:

Concentrative nucleoside transporters (CNTs): Na+-dependent symporters Equilibrative nucleoside transporters (ENTs): Na+-independent passive transporters The extracellular concentration of adenosine can be regulated by NTs, possibly in the form of a feedback loop connecting receptor signaling with transporter function.

Ectonucleotidases Released nucleotides can be hydrolyzed extracellularly by a variety of cell surface-located enzymes referred to as ectonucleotidases that control purinergic signalling. Extracellular nucleoside triphosphates and diphosphates are substrates of the ectonucleoside triphosphate diphosphohydrolases (E-NTPDases), the ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs) and alkaline phosphatases (APs). Extracellular AMP is hydrolyzed to adenosine by ecto-5'-nucleotidase (eN) as well as by APs. In any case, the final product of the hydrolysis cascade is the nucleoside.

Pannexins The Pannexin-1 channel (PANX1) is an integral component of the P2X/P2Y purinergic signaling pathway and the key contributor to pathophysiological ATP release. For example, the PANX1 channel, along with ATP, purinergic receptors, and ectonucleotidases, contribute to several feedback loops during the inflammatory response.

Purinergic signalling in humans

Circulatory system In the human heart, adenosine functions as an autacoid in the regulation of various cardiac functions such as heart rate, contractility, and coronary flow. There are currently four types of adenosine receptors found in the heart. After binding onto a specific purinergic receptor, adenosine causes a negative chronotropic effect due to its influence on cardiac pacemakers. It also causes a negative dromotropic effect through the inhibition of AV-nodal conduction. From the 1980s onwards, these effects of adenosine have been used in the treatment of patients with supraventricular tachycardia. The regulation of vascular tone in the endothelium of blood vessels is mediated by purinergic signalling. A decreased concentration of oxygen releases ATP from erythrocytes, triggering a propagated calcium wave in the endothelial layer of blood vessels and a subsequent production of nitric oxide that results in vasodilation. During the blood clotting process, adenosine diphosphate (ADP) plays a crucial role in the activation and recruitment of platelets and also ensures the structural integrity of thrombi. These effects are modulated by the P2RY1 and the P2Y12 receptors. The P2RY1 receptor is responsible for shape change in platelets, increased intracellular calcium levels and transient platelet aggregation, while the P2Y12 receptor is responsible for sustained platelet aggregation through the inhibition of adenylate cyclase and a corresponding decrease in cyclic adenosine monophosphate (cAMP) levels. The activation of both purinergic receptors is necessary to achieve sustained hemostasis.

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