Pharmacology of P2X receptors

Syed, Nawazish-i-Husain; Kennedy, Charles

doi:10.1002/wmts.1

Cited by 40 publications

(31 citation statements)

References 80 publications

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“…In contrast, a maximally effective concentration of AR-C69931MX (1 M) had no significant effect on contractions elicited by KCl (40 mM) (94.5 Ϯ 3.7% of control; n ϭ 6) or UDP (300 M) (95.7 Ϯ 1.5% of control; n ϭ 3). Our previous data indicated that P2X1 receptors mediate more than half of the response to ATP (Chootip et al, 2002(Chootip et al, , 2005, and, consistent with this, the contractions elicited by ATP (300 M) were virtually abolished by the combined blockade of P2X1 and P2Y 12 receptors with the P2X1 antagonist NF449 (30 M) (Syed et al, 2010;Syed and Kennedy, 2012) and AR-C69931MX (1 M) (Fig. 2, c and d).…”

Section: Atp-sensitivesupporting

confidence: 83%

Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Mitchell

Syed

Tengah

et al. 2012

J Pharmacol Exp Ther

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ATP and UDP constrict rat intrapulmonary arteries, but which receptors mediate these actions is unclear. Here, we used selective agonists and antagonists, along with measurements of P2Y receptor expression, to characterize the receptor subtypes involved. Isometric tension was recorded from endotheliumdenuded rat intrapulmonary artery rings (i.d. 200 -500 m) mounted on a wire myograph. Expression of P2Y receptor subtype expression was determined by using reverse transcriptionpolymerase chain reaction with receptor-specific oligonucleotide primers. The selective P2Y 1 agonist (N)-methanocarba-2-methylthioadenosine-5Ј-O-diphosphate (MRS2365) induced small, concentration-dependent contractions that were inhibited by the P2Y 1 antagonist N 6 -methyl-2Ј-deoxyadenosine-3Ј,5Ј-bisphosphate (MRS2179). Contractions evoked by ATP were unaffected by MRS2179, but inhibited by approximately one-third by the P2Y 12 antagonist N 6 -(2-methylthiomethyl)-2-(3,3,3-trifluoropropylthio)dichloro-methylene ATP (AR-C69931MX). Combined blockade of P2X1 and P2Y 12 receptors virtually abolished the response to ATP. ADP also evoked contractions that were abolished by AR-C69931MX. The selective P2Y 6 receptor agonist 3-(2-oxo-2-phenylethyl)-UDP (PSB 0474) evoked concentrationdependent contractions and was approximately three times more potent than UDP, but the P2Y 14 agonist UDP-glucose had no effect. Contractions evoked by UDP were inhibited by the P2Y 6 receptor antagonist N,NЈ-1,4-butanediylbis-NЈ-(3-isothiocyanatophenyl)thiourea (MRS2578), but not the cysteinyl leukotriene 1 (CysL 1 ) antagonist 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)thiopropanoic acid (MK571). Higher concentrations of MRS2578 inhibited contractions to KCl, so they were not studied further. mRNA for P2Y 1 , P2Y 6 , and P2Y 12 receptors was identified. Our working model is that P2Y 12 and P2X1 receptors are present in rat intrapulmonary arteries and together mediate ATP-induced vasoconstriction. Contractile P2Y 6 , but not P2Y 14 or CysLT 1 , receptors are also present and are a major site through which UDP evokes constriction.

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Section: Atp-sensitivesupporting

confidence: 83%

Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Mitchell

Syed

Tengah

et al. 2012

J Pharmacol Exp Ther

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“…For example, 3′-benzylamino-3′-deoxy-ATP was found to be very potent in the guinea-pig bladder, but was inactive at P2Y receptors. There are reviews that discuss the developments of P2X receptor antagonists [240,260,651].…”

Section: P2x Receptors Mediating Contraction Of the Bladdermentioning

confidence: 99%

Purinergic signalling in the urinary tract in health and disease

Burnstock

2013

Purinergic Signalling

142

149

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Purinergic signalling is involved in a number of physiological and pathophysiological activities in the lower urinary tract. In the bladder of laboratory animals there is parasympathetic excitatory cotransmission with the purinergic and cholinergic components being approximately equal, acting via P2X1 and muscarinic receptors, respectively. Purinergic mechanosensory transduction occurs where ATP, released from urothelial cells during distension of bladder and ureter, acts on P2X3 and P2X2/3 receptors on suburothelial sensory nerves to initiate the voiding reflex, via low threshold fibres, and nociception, via high threshold fibres. In human bladder t h e p u r i n e rg i c c o m p o n e n t o f p a r a s y m p a t h e t i c cotransmission is less than 3 %, but in pathological conditions, such as interstitial cystitis, obstructed and neuropathic bladder, the purinergic component is increased to 40 %. Other pathological conditions of the bladder have been shown to involve purinoceptor-mediated activities, including multiple sclerosis, ischaemia, diabetes, cancer and bacterial infections. In the ureter, P2X7 receptors have been implicated in inflammation and fibrosis. Purinergic therapeutic strategies are being explored that hopefully will be developed and bring benefit and relief to many patients with urinary tract disorders.

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“…Many P2XR antagonists have been identified [53–55], including a subtype non-selective, competitive antagonist called suramin. A mutational study [56] identified K138 in the human P2X1 receptor (corresponding to D141 in zP2X4R) as a possible suramin-interacting residue.…”

Section: P2x Receptorsmentioning

confidence: 99%

“…This lends support to the suggestion that competitive antagonists may occupy the wider inter-protomer ridge above the FCC (similar to ATP in the distal orientation), thereby maintaining the closure of the pre-M2 loop. Many other P2XR antagonists are described as noncompetitive, and their binding sites remain unknown [53–55]. …”

Section: P2x Receptorsmentioning

confidence: 99%

Size matters in activation/inhibition of ligand-gated ion channels

Dong

Zhou

2012

Trends in Pharmacological Sciences

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Cys-loop, glutamate, and P2X receptors are ligand-gated ion channels (LGICs) with 5, 4, and 3 protomers, respectively. There is now growing atomic-level understanding of their gating mechanisms. Although each family is unique in the architecture of the ligand-binding pocket, the pathway for motions to propagate from ligand-binding domain to transmembrane domain, and the gating motions of the transmembrane domain are similar. Here we review common features among the LGICs. In particular, agonists and competitive antagonists apparently induce opposite motions of the binding pocket. A simple way to control the motional direction is ligand size. Agonists, usually small, induce closure of the binding pocket, leading to opening of the channel pore, whereas antagonists, usually large, induce opening of the binding pocket, thereby stabilizing the closed pore. A cross-family comparison of the gating mechanisms of the LGICs, focusing in particular on the role played by ligand size, provides new insight on channel activation/inhibition and design of pharmacological compounds.

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Pharmacology of P2X receptors

Cited by 40 publications

References 80 publications

Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Purinergic signalling in the urinary tract in health and disease

Size matters in activation/inhibition of ligand-gated ion channels

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Pharmacology of P2X receptors

Cited by 40 publications

References 80 publications

Identification of Contractile P2Y1, P2Y6, and P2Y12Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Identification of Contractile P2Y1, P2Y6, and P2Y12Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Purinergic signalling in the urinary tract in health and disease

Size matters in activation/inhibition of ligand-gated ion channels

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Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Identification of Contractile P2Y₁, P2Y₆, and P2Y₁₂Receptors in Rat Intrapulmonary Artery Using Selective Ligands