New structure enlivens interest in P2X receptors

872

922

Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

“…Otherwise, only epithelial Na + channels and the acid-sensing ion channels reveal a similar membrane topology [121,122]. Such a membrane topology is unusual for ectoenzymes.…”

Section: Membrane Topologymentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

872

922

“…A common topology is shared by all subtypes-two transmembrane (TM) domains, a large cysteine-rich extracellular loop, an intracellular variable C-terminus, and a N-terminus [5,13,14]. The crystal structure of zebrafish P2X4 receptor revealed a trimer in the shape of a chalice, and each subunit adopted a dolphin-like shape with two TM domains and an extracellular loop resembling the fluke and body, respectively [15,16]. In primitive P2X receptors, the degree of ectodomain cysteine conservation varied greatly, while the trimer formation is still conserved suggested by previous work in Dictyostelium [7,8].…”

Section: Introductionmentioning

confidence: 99%

Comparative study of the P2X gene family in animals and plants

Hou

Cao

2016

P2X receptors are ligand-gated ion channels that can bind with the adenosine triphosphate (ATP) and have diverse functional roles in neuropathic pain, inflammation, special sense, and so on. In this study, 180 putative P2X genes, including 176 members in 32 animal species and 4 members in 3 species of lower plants, were identified. These genes were divided into 13 groups, including 7 groups in vertebrates and 6 groups in invertebrates and lower plants, through phylogenetic analysis. Their gene organization and motif composition are conserved in most predicted P2X members, while groupspecific features were also found. Moreover, synteny relationships of the putative P2X genes in vertebrates are conserved while simultaneously experiencing a series of gene insertion, inversion, and transposition. Recombination signals were detected in almost all of the vertebrates and invertebrates, suggesting that intragenic recombination may play a significant role in the evolution of P2X genes. Selection analysis also identified some positively selected sites that acted on the evolution of most of the predicted P2X proteins. The phenomenon of alternative splicing occurred commonly in the putative P2X genes of vertebrates. This article explored in depth the evolutional relationship among different subtypes of P2X genes in animal and plants and might serve as a solid foundation for deciphering their functions in further studies.

“…To date, eight subtypes of the P2Y receptors, belonging to the family of G protein coupled receptors (GPCRs), and seven subtypes (P2X1-7) of the P2X ion channels, permeable to Na + , K + , Ca ++ ions and small molecules, have been cloned from humans [1][2][3][4][5]. P2X receptors assemble as homo-or heterotrimers [6,7] and share a common structure, presenting intracellular N-and C-termini, two transmembrane domains (TM1 and TM2) and a large glycosylated and cysteine-rich extracellular domain [8][9][10]. When ATP binds to P2X receptors, a large conformational change causes the opening of the transmembrane pore allowing the cation flow and leading to the depolarization of the cell and generation of action potentials [11,12].…”

Section: Introductionmentioning

confidence: 99%

2′,3′-O-Substituted ATP derivatives as potent antagonists of purinergic P2X3 receptors and potential analgesic agents

Ben

Marchenkova

Thomas

et al. 2016

Blocking membrane currents evoked by the activation of purinergic P2X3 receptors localized on nociceptive neurons represents a promising strategy for the development of agents useful for the treatment of chronic pain conditions. Among compounds endowed with such antagonistic action, 2′,3′-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) is an ATP analogue, whose inhibitory activity on P2X receptors has been previously reported. Based on the results of molecular modelling studies performed with homology models of the P2X3 receptor, novel adenosine nucleotide analogues bearing cycloalkyl or arylalkyl substituents replacing the trinitrophenyl moiety of TNP-ATP were designed and synthesized. These new compounds were functionally evaluated on native P2X3 receptors from mouse trigeminal ganglion (TG) sensory neurons using patch clamp recordings under voltage clamp configuration. Our data show that some of these molecules are potent (nanomolar range) and reversible inhibitors of P2X3 receptors, without any apparent effect on trigeminal GABA A and 5-HT 3 receptors, whose membrane currents were unaffected by the tested compounds.