The purinergic neurotransmitter revisited: A single substance or multiple players?

Abstract

The past half century has witnessed tremendous advances in our understanding of extracellular purinergic signaling pathways. Purinergic neurotransmission, in particular, has emerged as a key contributor in the efficient control mechanisms in the nervous system. The identity of the purine neurotransmitter, however, remains controversial. Identifying it is difficult because purines are present in all cell types, have a large variety of cell sources, and are released via numerous pathways. Moreover, studies on purinergic neurotransmission have relied heavily on indirect measurements of integrated postjunctional responses that do not provide direct information for neurotransmitter identity. This paper discusses experimental support for adenosine 5′-triphosphate (ATP) as a neurotransmitter and recent evidence for possible contribution of other purines, in addition to or instead of ATP, in chemical neurotransmission in the peripheral, enteric and central nervous systems. Sites of release and action of purines in model systems such as vas deferens, blood vessels, urinary bladder and chromaffin cells are discussed. This is preceded by a brief discussion of studies demonstrating storage of purines in synaptic vesicles. We examine recent evidence for cell type targets (e.g., smooth muscle cells, interstitial cells, neurons and glia) for purine neurotransmitters in different systems. This is followed by brief discussion of mechanisms of terminating the action of purine neurotransmitters, including extracellular nucleotide hydrolysis and possible salvage and reuptake in the cell. The significance of direct neurotransmitter release measurements is highlighted. Possibilities for involvement of multiple purines (e.g., ATP, ADP, NAD+, ADP-ribose, adenosine, and diadenosine polyphosphates) in neurotransmission are considered throughout.

Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut

“…ATP (20), NAD + (14,15,21), and adenosine 5′-diphosphate ribose (ADPR) (17) activate P2Y1R and SK channels and might be inhibitory neurotransmitters in the colon (22). Because Up4A appears to stimulate P2Y1Rs in endothelium, and P2Y1Rs are important for purinergic signaling in the colon, we investigated whether Up4A is released in colonic muscle, whether Up4A affects membrane potentials and contractions of colonic muscles, whether Up4A is an agonist for P2Y1R, whether cells expressing PDGF receptor α (PDGFRα) are targets of Up4A, and how Up4A is metabolized in colons of humans and mice.…”

Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling

“…3b). Recent literature has shown that NAD + is stored in secretory granules and released from nerve endings in visceral smooth muscles and acts as an inhibitory neurotransmitter [41,42]. However, involvement of the SLC17A9 protein in the vesicular storage of NAD + is unlikely, because it does not recognize NAD + as a transport substrate [Sawada and Moriyama, unpublished observation].…”

Purinergic P2Y1 Receptors Control Rapid Expression of Plasma Membrane Processes in Hippocampal Astrocytes

“…Astrocytes are known to release significant amounts of ATP in physiological and pathological conditions through different pathways (as reviewed in [37]). One possible ATP secretion pathway is represented by gap junctions.…”

“…Among neurotransmitters, purines and mainly ATP, abundantly released by glial cells, have emerged as key contributors in the control of central functions [22][23][24]. ATP release might occur in several different ways: vesicular exocytosis [25][26][27][28], through anion channels [29][30][31][32], ATP-activated channel P2X7 [33], connexin hemichannels [34][35][36] (for review see [37]). Several conditions might determine ATP release: stimulation of ionotropic glutamate receptors in astrocytes [38]; intracellular Ca2+ increase [39]; mechanical stimulation [40]; bradykinin stimulation [41].…”