Physiology and Pathophysiology of Purinergic Neurotransmission

Abstract

This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.

Inhibitory effect of estrogen receptor beta on P2X3 receptors during inflammation in rats

“…ATP and P2X3R have a long history of involvement with pain and inflammation [21,22]. In colitis, more internal ATP was produced and expression of P2X3R at the end of colorectal nerves was also increased, thus leading to hypersensitivity of rectocolon [23][24][25].…”

Neuroprotective roles of the P2Y2 receptor

“…P2Rs (both P2X ligandgated cation channels and P2Y G protein-coupled receptors) [1,4,6] are expressed in neuroglia (astrocytes, oligodendrocytes) and microglia of the CNS [14], where they regulate differentiation, nociceptive transmission, cytokine release, apoptosis, and metalloprotease-dependent degradation of amyloid precursor protein (APP) [16,27,31,[38][39][40]. Among cell types that comprise the CNS, mRNAs for P2X1-7 and P2Y 1,2,4,6,11,12,13,14 receptor subtypes have been identified in primary rat astrocytes [4,[41][42][43][44], and their expression patterns can vary with the age of the animal [45,46]. Neurons express mRNAs for P2X3, 5-7 and P2Y 1,2,4,6,12,13 receptors [12,[47][48][49].…”

“…It has become apparent that P2 receptors for extracellular nucleotides are ubiquitously expressed in a wide variety of tissues, and the complexity of responses to nucleotides is due in large part to the presence of multiple subtypes of P2X receptor ligand-gated ion channels and G protein-coupled P2Y receptors [1][2][3][4][5][6][7]. This functional complexity is well manifested in the central nervous system (CNS) where 7 P2X and 8 P2Y receptor subtypes are expressed under a range of conditions in several different interacting cell types [6,[8][9][10][11][12].…”

“…Accordingly, studies on P2 receptor functions in the brain must consider the combined contributions of P2X and P2Y receptors expressed in neurons, microglial cells, astrocytes, and endothelium [10,[13][14][15]. In addition, the major ligand that activates many of these P2 receptor subtypes is ATP, released in the course of neurotransmission or under proinflammatory or cell apoptotic conditions [1,[16][17][18]. Since ATP or its degradative products activate most of the P2 nucleotide and P1 adenosine receptor subtypes identified in the CNS [1], unraveling the effects of ATP in vivo is difficult.…”

“…In addition, the major ligand that activates many of these P2 receptor subtypes is ATP, released in the course of neurotransmission or under proinflammatory or cell apoptotic conditions [1,[16][17][18]. Since ATP or its degradative products activate most of the P2 nucleotide and P1 adenosine receptor subtypes identified in the CNS [1], unraveling the effects of ATP in vivo is difficult. This analysis can be simplified using animal models with selective knockout of specific P2 receptor subtypes or subtype-selective agonists/antagonists when available.…”