ATP as a cotransmitter in the autonomic nervous system

Abstract

The role of adenosine 5'-triphosphate (ATP) as a major intracellular energy source is well-established. In addition, ATP and related nucleotides have widespread extracellular actions via the ionotropic P2X (ligand-gated cation channels) and metabotropic P2Y (G protein-coupled) receptors. Numerous experimental techniques, including myography, electrophysiology and biochemical measurement of neurotransmitter release, have been used to show that ATP has several major roles as a neurotransmitter in peripheral nerves. When released from enteric nerves of the gastrointestinal tract it acts as an inhibitory neurotransmitter, mediating descending muscle relaxation during peristalsis. ATP is also an excitatory cotransmitter in autonomic nerves; 1) It is costored with noradrenaline in synaptic vesicles in postganglionic sympathetic nerves innervating smooth muscle preparations, such as the vas deferens and most arteries. When coreleased with noradrenaline, ATP acts at postjunctional P2X1 receptors to evoke depolarisation, Ca(2+) influx, Ca(2+) sensitisation and contraction. 2) ATP is also coreleased with acetylcholine from postganglionic parasympathetic nerves innervating the urinary bladder and again acts at postjunctional P2X1 receptors, and possibly also a P2X1+4 heteromer, to elicit smooth muscle contraction. In both cases the neurotransmitter actions of ATP are terminated by dephosphorylation by extracellular, membrane-bound enzymes and soluble nucleotidases released from postganglionic nerves. There are indications of an increased contribution of ATP to control of blood pressure in hypertension, but further research is needed to clarify this possibility. More promising is the upregulation of P2X receptors in dysfunctional bladder, including interstitial cystitis, idiopathic detrusor instability and overactive bladder syndrome. Consequently, these roles of ATP are of great therapeutic interest and are increasingly being targeted by pharmaceutical companies.

Characterisation of P2Y2 receptors in human vascular endothelial cells using AR‐C118925XX, a competitive and selective P2Y2 antagonist

“…Currently, potent, selective antagonists have only been developed for P2Y 1 (e.g., MRS2179, MRS2279, and MRS2500) and P2Y 12 (e.g., ticagrelor, cangrelor, and clopidogrel) receptors (see Abbracchio et al, ; Kennedy et al, ). These played a major role in identifying physiological roles, such as that of P2Y 1 receptors in peristalsis in the gut (see Kennedy, ) and of P2Y 1 and P2Y 12 receptors in platelet aggregation (Abbracchio et al, ; von Kügelgen, ). Clearly, the development of potent and selective antagonists at the other P2Y subtypes would greatly enhance our ability to determine their functions in health and disease.…”

Downregulation of P2Y12 in the superior cervical ganglia alleviates abnormal sympathetic activity after myocardial ischemia

“…The heart is innervated by the sympathetic and parasympathetic nervous systems (Kennedy, ; Kennedy et al, ; Pather et al, ). The cardiac sympathetic afferent nerve endings are activated during MI (Li & Pan, ; Li et al, ; Zhang et al, ; Zou et al, ).…”

“…Adenosine 5'-triphosphate (ATP) is an important neurotransmitter and neuromodulator (Burnstock & Pelleg, 2015;Burnstock, 2006;Erlinge & Burnstock, 2008). By acting on P2 receptors, ATP can modulate cardiac function (Burnstock & Pelleg, 2015;Erlinge & Burnstock, 2008;Gourine, Wood, & Burnstock, 2009;Kennedy, Chootip, Mitchell, Syed, & Tengah, 2013;Kennedy, 2015;Vassort, 2001). P2 receptors include ionotropic P2X receptors (ATP-gated ion channels) and metabotropic P2Y receptors (Gprotein-coupled receptors) (Abbracchio et al, 2005;Burnstock & Kennedy, 1985;Burnstock & Pelleg, 2015;Erlinge & Burnstock, 2008;Gourine, Wood, & Burnstock, 2009;Kennedy et al, 2013;Kennedy, 2015;Khakh & Humphrey, 2001;Vassort, 2001).…”

Extracellular ATP: An Essential Apoplastic Messenger in Plants

“…A series of biochemical reactions occurs downstream of second messengers, including the phosphorylation and dephosphorylation of structural and catalytic proteins, as well as the activation of transcription factors and the genes they promote. These reactions induce changes in cell metabolism and development, which can eventually lead to changes in the structure and function of the entire body (reviewed by Ralevic and Burnstock 1998;Burnstock 2006Burnstock , 2007Burnstock et al 2013;Idzko et al 2014;Kennedy 2015;Cavaliere et al 2015;Ferrari et al 2015).…”

“…eATP is secreted from the cell through secretory vesicles generated in the Golgi apparatus or through transporters in the plasma membrane (PM). Deregulation of secretion can lead to abnormal levels of eATP, which in turn causes cell death, uncontrolled cell division, and aberrant cell differentiation, and can result in serious illness in animals and humans (reviewed by Ralevic and Burnstock 1998;Burnstock 2006Burnstock , 2007Burnstock et al 2013;Idzko et al 2014;Kennedy 2015;Cavaliere et al 2015;Ferrari et al 2015).…”