Purinergic signalling
[6] Among invertebrates, the purinergic signalling system has been found in bacteria, amoeba, ciliates, algae, fungi, anemones, ctenophores, platyhelminthes, nematodes, crustacea, molluscs, annelids, echinoderms, and insects.
[9] The primitive P2X receptors of unicellular organisms often share low sequence similarity with those in mammals, yet they still retain micromolar sensitivity to ATP.
[14] Released nucleotides can be hydrolyzed extracellularly by a variety of cell surface-located enzymes referred to as ectonucleotidases that control purinergic signalling.
[19] After binding onto a specific purinergic receptor, adenosine causes a negative chronotropic effect due to its influence on cardiac pacemakers.
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.
[22][23] 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.
[29] Like most immunomodulating agents, ATP can act either as an immunosuppressive or an immunostimulatory factor, depending on the cytokine microenvironment and the type of cell receptor.
[21] In the central nervous system (CNS), ATP is released from synaptic terminals and binds to a plethora of ionotropic and metabotropic receptors.
[36] In the peripheral nervous system, Schwann cells respond to nerve stimulation and modulate the release of neurotransmitters through mechanisms involving ATP and adenosine signalling.
[37] In the retina and the olfactory bulb, ATP is released by neurons to evoke transient calcium signals in several glial cells such as Muller glia and astrocytes.
Although purinergic signaling has been connected to pathological processes in the context of neuron-glia communication, it has been revealed, that this is also very important under physiological conditions.
Microglial processes specifically recognize these purinergic somatic-junctions, and monitor neuronal functions by sensing purine nucleotides via their P2Y12-receptors.
[40] During neurogenesis and in early brain development, ectonucleotidases often downregulate purinergic signalling in order to prevent the uncontrolled growth of progenitor cells and to establish a suitable environment for neuronal differentiation.
[42] In the kidneys, the glomerular filtration rate (GFR) is regulated by several mechanisms including tubuloglomerular feedback (TGF), in which an increased distal tubular sodium chloride concentration causes a basolateral release of ATP from the macula densa cells.
[45] Extracellular ATP signals acting on glial cells and the neurons of the respiratory rhythm generator contribute to the regulation of breathing.
[54][55] The release of ATP increases adenosine levels and activates nitric oxide synthase, both of which induces the relaxation of the corpus cavernosum penis.
[56][57] The bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis contains a higher concentration of ATP than that of control subjects.
[65][66][67] Electroacupuncture may inhibit pain by the activation of a variety of bioactive chemicals through peripheral, spinal, and supraspinal mechanisms of the nervous system.
[70] Theophylline was originally used as a bronchodilator, although its usage has declined due to several side effects such as seizures and cardiac arrhythmias caused by adenosine A1 receptor antagonism.
Regadenoson, a vasodilator which acts on the adenosine A2A receptor, was approved by the United States Food and Drug Administration in 2008 and is currently widely used in the field of cardiology.
It is understood that shifting the balance between purinergic P1 and P2 signalling is an emerging therapeutic concept that aims to dampen pathologic inflammation and promote healing.
[13][85] In the 1960s, the classical view of autonomic smooth muscle control was based upon Dale's principle, which asserts that each nerve cell can synthesize, store, and release only one neurotransmitter.
[86] Beginning in 1972, Geoffrey Burnstock ignited decades of controversy after he proposed the existence of a non-adrenergic, non-cholinergic (NANC) neurotransmitter, which he identified as ATP after observing the cellular responses in a number of systems exposed to the presence of cholinergic and adrenergic blockers.
[87][88][89] Burnstock's proposal was met with criticism, since ATP is an ubiquitous intracellular molecular energy source[90] so it seemed counter-intuitive that cells might also actively release this vital molecule as a neurotransmitter.
[1] Today, purinergic signalling is no longer considered to be confined to neurotransmission, but is regarded as a general intercellular communication system of many, if not all, tissues.
