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Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
1The screen versions of these slides have full details of copyright and acknowledgements
1
Prof. Geoffrey Burnstock PhD, DSc, FMedSci, FRS
Director of the Autonomic Neuroscience Institute Royal Free Hospital School of Medicine, London, UK
Department of Pharmacology and TherapeuticsThe University of Melbourne, Australia
Purinoceptors and Fast Purinergic Transmission
at Neuromuscular Junctions and Synapses
2Non-synaptic autonomic neuromuscular transmission
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Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
2The screen versions of these slides have full details of copyright and acknowledgements
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Innervation of mast cells
Rat dura mater
Rat intestine muscularis mucosa Rabbit middle cerebral artery
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Taenia coli
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Taenia coli – IJP’s
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
3The screen versions of these slides have full details of copyright and acknowledgements
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Criteria for establishing a neurotransmitter:
1. Synthesis and storage in nerve terminals
2. Release by a Ca2+-dependent mechanism
3. Mimicry of the neurogenic response by receptor occupation
4. Inactivation by ectoenzymes and/or neuronal uptake
5. Modification of response by drugs in a comparable manner to that of the neurogenic response
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
4The screen versions of these slides have full details of copyright and acknowledgements
10Albert Szent-Györgyi Pamela Holton
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Myenteric neurones - quinacrine
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Bladder - NANC
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
5The screen versions of these slides have full details of copyright and acknowledgements
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Ectonucleotidases
From Zimmermann, 2001
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Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
6The screen versions of these slides have full details of copyright and acknowledgements
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Purinergic nerve
Burnstock 1972, Pharm Revs 24: 509-581
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“A busy bee called ATP Whose wings were full of energy, Who worked and built inside a cellEmerged to see what he could tell
To each and every other cell.”
(Part of a poem by Nomi Burnstock, reproduced from Journal of the Autonomic Nervous System, Special Issue: Purines and the autonomic nervous system: from controversy to clinic; prologue, 81: 1-2 (2000) with permission from Elsevier)
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
7The screen versions of these slides have full details of copyright and acknowledgements
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Vas deferens – sympathetic nerve stimulation
From Burnstock and Holman, 1960
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
8The screen versions of these slides have full details of copyright and acknowledgements
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Vas deferens – EJP’s
From Sneddon and Burnstock, 1984
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Guinea pig vas deferens – spritz 20ms
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Isolated rabbit saphenous artery
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
9The screen versions of these slides have full details of copyright and acknowledgements
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Rat tail artery (sympathetic cotransmission)
From Sneddon & Burnstock 1984 (A-C) and Jobling and McLachlan, 1992 (D)
D
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Schematic of sympathetic cotransmission
From Burnstock & Verkhratsky, 2010
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Pre- and post junctional neuromodulation by neuropeptide Y (NPY)
depends on junctional cleft width
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
10The screen versions of these slides have full details of copyright and acknowledgements
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Sympathetic cotransmission in SHR
• Vidal, Hicks & Langer (1986) Naunyn-Schmiedeberg’sArch. Pharmacol. 332: 384-390“our results suggest a significantly greater co-transmitter role for ATP with noradrenaline on tail arteries of SHR compared with control normotensive WKY rats...”
• Bullock & McGrath (1992) Br. J. Pharmacol. 107 (S): 145P“Evidence for increased purinergic contribution in hypertensive blood vessels exhibiting cotransmission”
• Brock & Van Helden (1995) Pflügers Arch. – Eur. J. Physiol. 430: 901-908“Enhanced excitatory junction potentials in mesenteric arteries from spontaneously hypertensive rats”
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Increase in purinergic component of nerve-mediated responses of human bladder
in pathological conditions
• Interstitial cystitis (40% purinergic)Palea et al., J. Urol. 150: 2007-2012, 1993
• Outflow obstruction (25% purinergic)Smith & Chapple, Neurol. Urodyn. 13: 414-415, 1994
• Neurogenic bladder (40% purinergic)Wammack et al., Akt. Urol. 26: 16-18, 1995
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
11The screen versions of these slides have full details of copyright and acknowledgements
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Sensory - motor nerves
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Quinacrine NADPH-d
From Belai and Burnstock, 1994
33- -
Gut – NANC inhibitory nerves
VIP NO ATP
ATP ADPG
VIP
NO=
== = 8-PTRB2
L-NAME
+ - -(slow)(slow) (slow)(v.slow) (fast)
FenoprofenIndomethacin
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
12The screen versions of these slides have full details of copyright and acknowledgements
34
Skeletal neuromuscular junction
35Cell Membrane Receptors for Drugs and Hormones: A Multidisciplinary Approach, edited by R.W. Straub and L. Bolis. Raven Press, New York © 1978
AntagonistsAgonist
potencies
Changes in cAMP
production
Induction of prostaglandin
synthesis
P1 Methylxanthines AD≥AMP>ADP≥ATP YES NO
P2Quinidine
Imidazolines
2’2 Pyridilisatogen
ATP≥ADP>AMP≥AD NO YES
36Modified from Burnstock, 1972, Pharm Revs 24, 509-58136
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
13The screen versions of these slides have full details of copyright and acknowledgements
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Loewi-inspired experiments (1966)
● = nerve stimulation (5 Hz for 40 sec every 6 mins at 50 V and 2 msec duration)
=
=
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P1receptor Agonists Antagonists
Transductionmechanism Patent utility
A1
CCPA > R-PIA = S-ENBACVT-510GR79236
DPCPXN-0840
MRS1754WRC-0571
Gi/o
cAMP ↓PLC ↑
Atrial fibrillationCardioprotection
DiabetesIschaemia
A2A
HENECA > CGS21680 =
CVT-3146ATL-146e
KF17837SCH 58261ZM241385KW 6002
GS
cAMP ↑IP3 ↑
InflammationAsthmaCOPD
Parkinson’s Disease
A2B Bay60-6583
PBS603MRE-2029-F20
PSB0788MRS 1706PSB 1115Alloxazine
GS
cAMP ↑PLC ↑
Bowel and bladder abnormalities
A3
IB-MECA > 2-Cl-IB-MECA
DBXRMVT160
HEMADO
MRS1220L-268605
MRS 1191 & 1334 (h)MRS 1523 (r)
VUF 8504 & 5574PSB10
Gi/o
Gq/11
cAMP ↓IP3 /DAG ↑
PLC ↑
CardioprotectionCerebrovascular
IschaemiaCancer,Allergy
39• Subtype 1 (designated P2X)
• Subtype 2 (designated P2Y)
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
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Initial cloning of P2 receptors
P2YP2Y1: Webb TE, Simon J, Krishek BJ, Bateson AN, Smart TG, King BF,
Burnstock G and Barnard EA. Cloning and functional expression of a brain G-protein-coupled ATP receptor, FEBS Lett 324: 219-225, 1993
P2Y2: Lustig KD, Shiau AK, Brake AJ and Julius D. Expression cloning of an ATP receptor from mouse neuroblastoma cells, Proc Nat Acad Sci USA 90: 5113-5117, 1993
P2XP2X1: Valera S, Hussy N, Evans RJ, Adami N, North RA, Surprenant A and Buell G.
Cloning and expression of the P2X receptor for extracellular ATP reveals a new class of ligand-gated ion channel, Nature 371: 516-519, 1994
P2X2: Brake AJ, Wagenbach MJ and Julius D. New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor, Nature 371: 519-523, 1994
41From Fields & Burnstock, 2006, Nature Neuroscience
42From North, 1996
≠
≈
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
15The screen versions of these slides have full details of copyright and acknowledgements
43From Kawate et al., 2009 – Eric Gouaux
Crystal structure of P2X4 receptor
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NeurotransmitterReceptors
Fast ionotropic(Ligand-gated ion channels)
Slow metabotropic(G-Protein)
AchNicotinic
muscle typeneuronal type
MuscarinicM1 → M5
GABA GABA A GABAB
GlutamateAMPA
KainateNMDA
mGlu1↓
mGlu7
5-HT 5-HT35-HT1A-F, 5-HT2A-C, 5-HT4,
5-HT5A-B, 5-HT6, 5-HT7
ATP P2XP2X1→P2X7
P2YP2Y1, P2Y2, P2Y4, P2Y6, P2Y11,
P2Y12, P2Y13, P2Y14
NA ─ α1, α2, β
Glycine α1, α2, α3 ─
From Burnstock, 1996
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Receptor Main distribution Agonists Antagonists
P2X1
Smooth muscle, platelets, cerebellum,
dorsal horn spinal neurones
L-βγ-meATP≥α,β-meATP = ATP = 2-MeSATP
PAPET-ATP(rapid desensitization)
TNP-ATP, IP5I, NF023, NF449
RO1, RO 0437626, NF279, MRS2159
P2X2
Smooth muscle, CNS, retina, chromaffincells,
autonomic and sensory ganglia
ATP≥ATPγS≥2-MeSATP>>α,β-meATP, β,γ-CF2ATP
(pH + zinc sensitive)
Suramin, RB2, NF770,isoPPADS, PSB-1011, NF778,
aminoglycoside
P2X3Sensory neurones,
NTS, some sympathetic neurones
2-MeSATP≥ATP≥α,β-meATP =Ap4A, PAPET-ATP
(rapid desensitization)
TNP-ATP, isoPPADS A317491, NF110, RO4, RN-1838,
spinorphin, AF353
P2X4 CNS, testis, colon ATP>α,β-meATP, CTPIvermectin (potentiates)
TNP-ATP & BBG (weak),BBG, Paroxetine, 5-BDBD, CORM
2, phenolphthalein
P2X5Proliferating cells in skin,
gut, bladder, thymus, spinal cord
ATPγSAp4AGTP
Suramin, PPADS,BBG
P2X6 CNS, motor neurones in spinal cord
─ (does not function as homomultimer) ─
P2X7Apoptotic cells in immune cells,
pancreas, skin etc.
BzATP>ATP≥2-MeSATP>α,β-meATP
KN62, KN04, MRS2427, BBG, o-ATP, Decavanadate, A-804598,
RN-6189, AZD-9056, AZ10606120, A740003, A-438079, GSK-1370319
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
16The screen versions of these slides have full details of copyright and acknowledgements
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Heteromultimer coexpression studies
• P2X2/3 - Lewis et al., 1995; Radford et al., 1997
• P2X4/6 - Lé et al., 1998
• P2X1/5 - Torres et al., 1998; Haines et al., 1999
• P2X2/6 - King et al., 2000
• P2X1/2 - Brown et al., 2002
• P2X1/4 - Nicke et al., 2005
• P2X4/7? - Guo et al., 2007
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Receptor Main distribution Agonists Antagonists Transduction mechanisms
P2Y1
Epithelial and endothelial cells, platelets, immune cells,
osteoclasts
MRS2365=(N)-me-2-MeSADP>2-MeSADP>
ADP=ADPβS>ATP
MRS2179MRS2500
Gq/G11; PLCβactivation
P2Y2Immune,epithelial & endothelial
cells, kidney tubules, osteoblasts
UTP=ATPUTP-γ-S
INS 37217(Up4dc)
Suramin > RB2AR-C126313
Gq/G11 and possibly Gi;
PLCβ activation
P2Y4 Endothelial cells UTP≥ATPUTP-γ-S RB2 > suramin
Gq/G11 and possibly Gi;
PLCβ activation
P2Y6 Some epithelial cells, placenta, T-cells, thymus
UDP>>UTP>>ATPUDP-β-S
MRS2578 Gq/G11; PLCβactivation
P2Y11 Spleen, intestine, granulocytes ARC67085MX>BzATP≥ATPγS>ATP
Suramin > RB2NF340,
5’-AMPS
Gq/G11 and GS; PLCβ activation
P2Y12 Platelets, glial cells 2-MeSADP>ADP>>ATP
ARC69931MXCT50547, AZD6140
INS49266,MRS2395
Gi/Go; Inhibition
of adenylate cyclase
P2Y13Spleen, brain, lymph nodes,
bone marrowADP=2meSADP>>ATP
and 2meSATP MRS2211 Gi/Go
P2Y14
Placenta, adipose tissue, stomach, intestine,
discrete brain regions
UDP glucose = UDP-galactose Gq/G11
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• Agboh, K.C., Webb, T.E., Evans, R.J. & Ennion, S.J. (2004) Functional characterization of a P2X receptor from Schistosoma mansoni,Journal of Biological Chemistry 279: 41650-41657
• Fountain, S.J., Parkinson, K., Young, M.T., Cao, L., Thompson, C.R. & North, R.A. (2007) An intracellular P2X receptor required for osmoregulation in Dictyostelium discoideum, Nature 448: 200-203
• Fountain, S.J., Cao, L., Young, M.T. & North, R.A. (2008) Permeation properties of a P2X receptor in the green algae Ostreococcus tauri, J Biol Chem. 283: 15122-15126
• Burnstock, G. & Verkhratsky, A. (2009) Evolutionary origins of the purinergic signalling system, Acta Physiologica 195: 415-447
• Fountain, S.J. & Burnstock, G. (2009)An evolutionary history of P2X receptors, Purinergic Signalling 5: 269-272
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
17The screen versions of these slides have full details of copyright and acknowledgements
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• Evans, R.J., Derkach, V. and Suprenant, A. (1992) ATP mediates fast synaptic transmission in mammalian neurons, Nature 357: 503-505
• Silinsky, E.M., Gerzanich, V. and Vanner, S.M. (1992)ATP mediates excitatory synaptic transmission in mammalian neurones, British Journal of Pharmacology 106: 762-763
• Edwards, F.A., Gibb, A.J. and Colquhoun, D. (1992)ATP receptor-mediated synaptic currents in the central nervous system, Nature 359: 144-146
50
Purinergic sympathetic transmission in coeliac neurons / suramin
From Evans et al., 1992
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Intrinsic neurons in bladder and heart
From Burnstock et al., 1987
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
18The screen versions of these slides have full details of copyright and acknowledgements
52From Galligan, 2002
Guinea-pig small intestine non-cholinergic fast excitatory synaptic pathways
Current Opinion in Pharmacology
53From Barajas-López et al., 1996
ATP activates single channel activity in membrane patches of guinea-pig myenteric neurons
54From Galligan, 2002
Guinea-pig intestine slow excitatory synaptic pathways
Current Opinion in Pharmacology
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
19The screen versions of these slides have full details of copyright and acknowledgements
55From Barajas-López et al., 1994
Guinea-pig submucosal neurons
56From Burnstock, 2008
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P2X3 – IR synapse; dorsal horn: C6: rat
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
20The screen versions of these slides have full details of copyright and acknowledgements
58
Spontaneous EPSC’s in cortical neurons mediated by P2X4 receptors
Modified from Lalo et al., 2007
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P2XR-mediated synaptic EPSC’s in cortical (a) and hippocampal (b) neurons
From Pankratov et al., 2002 (a) and 1998 (b)
a: 1 = Control EPSC’s2 = Glutamate antagonists3 = ACh (Nicotinic) antagonist4 = P2XR antagonist5 = washout
b: 1 and 2 = Glutamate antagonists3 = PPADS (P2R antagonist)
60Modified from Pankratov et al.,2009
P2XR-dependent regulation of synaptic plasticity in the CNS
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
21The screen versions of these slides have full details of copyright and acknowledgements
61From Sawada et al., 2008
Vesicular nucleotide transporter (VNUT)
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• A P2X purinoceptor expressed by a subset of sensory neurons C-Chen , AN Akopian, L Sivilotti, D Colquhoun, G Burnstock, JN Wood, Nature 1995, 377: 428-431
• Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neuronsC Lewis, S Neldhart, C Holy, RA North, A SuprenantNature, 1995 377: 432-435
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
22The screen versions of these slides have full details of copyright and acknowledgements
64From: Burnstock, 1996 ‘A unifying purinergic hypothesis for the initiation of pain’ Lancet, 347, 1604-1605
Sources of ATP acting on nociceptive purinoreceptors at sensory nerve terminals
Sympathetic nerveTerminal varicosities
Endothelial cellsof microvessels
Tumor cellsVasodilatation
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P2X3 receptors are expressed in GDNF but not NGF sensitive neurons
% o
f cel
ls
expr
essi
ng P
2X3
0
20
40
60
80
CGRP IB4 NF200
66 From Burnstock and Wood, 1996
Sympathetic nerve Merkel cell
Endothelial cell
Tumor cell
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
23The screen versions of these slides have full details of copyright and acknowledgements
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Schematic of purinergic mechano-sensory transduction
In TUBES e.g., ureter, vagina, salivary & bile ducts, gut & SACS, e.g., urinary & gall bladder, & lung
From Burnstock, 1999
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Discharges in the pelvic nerve induced by distension of the bladder in P2X3 KO mouse and its WT control
WT mouse P2X3 knock-out mouse
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69 Nature 2000, 407: 1011
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
24The screen versions of these slides have full details of copyright and acknowledgements
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Guinea-pig ureter –antagonism of distension response by TNP-ATP
From Rong & Burnstock, 2004
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Human ureter ATP release
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Colo-rectum: effect of ATP in sensory nerve activity
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Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
25The screen versions of these slides have full details of copyright and acknowledgements
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Distension of rat colo-rectum: ATP release
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Guinea-pig colon: P2X3 immunoreactivity in a whole-mount preparation of the subepithelial nerve plexus
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Hypothesis:Purinergic sensory pathways in gut
Powerful distensionATP release → stimulation of high threshold extrinsic sensory nociceptive fibres → pain
Subepithelial sensorynerve plexus(with P2X3 receptors)
Moderate distensionATP release → stimulation of low threshold intrinsic sensory fibres → peristaltic reflexes
Extrinsic sensory nerves
P2X3Calbindin
Intrinsic sensory nerves
DRG
P2X3IB4
ATPATP
ATPATP
ATP
ATPATP ATP
ATP
ATP
Spinal cord & brain pain centres
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
26The screen versions of these slides have full details of copyright and acknowledgements
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Sensory nerves in human tooth pulp and odontoblasts - P2X3
From Alavi et al., 2001
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Innervation of neuroepithelial bodies
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Hypothesis: purinergic signalling in acupuncture
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
27The screen versions of these slides have full details of copyright and acknowledgements
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Rat tongue – sensory nerve preparation
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Rat colitis model, using trinitrobenzenesulfonic acid (TNBS) enema
<
=
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ATP concentration in luminal fluid samples from normal and inflamed rat colo-rectum
during distension
Values are means ± SE
0.0
2.5
5.0
7.5
10.0
12.5Normal
Colitis
Pressure (mmHg)
ATP
(pm
ol/m
l)
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
28The screen versions of these slides have full details of copyright and acknowledgements
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Selective antagonists with drug-like properties(e.g., orally bioavailable, metabolically stable)
From Gever et al., 2006
“Drug-like” antagonists
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
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Number of papers published on P2 purinergic signalling
between 1972 and end of 2012
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Associate EditorsMolecular Biology of Purinergic ReceptorsSimon Robson, Boston, USAJean-Marie Boeynaems, Brussels, BelgiumEctoenzymesHerbert Zimmermann, Frankfurt, GermanyMedicinal Chemistry & PharmacologyKenneth A Jacobson, Bethesda, USAAd Ijzerman, Leiden, The NetherlandsPathophysiology & Clinical ImplicationsMichael F Jarvis, Chicago, USAJim Wiley, Melbourne, Australia
Development & RegenerationKazuhide Inoue, Tokyo, JapanPhysiological RolesFrancesco Di Virgilio, Ferrara, ItalyPeter Illes, Leipzig, Germany Vera Ralevic, Nottingham, UKTim Arnett, London, UKJean-Pierre Timmermans, Antwerp, BelgiumReviewsMaria Abbracchio, Milan, ItalyNick Dale, Coventry, UK
Editorial Board Jolanta Baranska, Warsaw, PolandLuiz Belardinelli, Palo Alto, USAMax Bennett, Sydney AustraliaMichael Blackburn, Houston, TexasStefan Boehm, Vienna, AustriaPier Borea, Ferrara, ItalyRichard C Boucher, Chapel Hill, USAJose Boyer, Durham, USAGloria Cristalli, Camerino, ItalyBruce Cronstein, New York City, USARodrigo Cunha, Coimbra, PortugalJeff Dixon, London, OntarioGeorge Dubyak, Cleveland, USADavid Erlinge, Lund, SwedenAnthony Ford, Palo AltoJohn Fozard, Basel, Switzerland
Christian Gachet, Strasbourg, FranceKen Harden, Chapel Hill, USA,Stephen Holgate, Southampton, UKGary Housley, Auckland, New ZealandPablo Huidobro-Toro, Santiago, ChilePaul Insel, San Diego, USACharles Kennedy, Strathclyde, UKBaljit Khakh, Cambridge, UKYong-Chul Kim, Kwangju, KoreaOleg Kristal, Kiev, UkraineEduardo Lazarowski, North Carolina, USAJoel Linden, Charlottesville, USAMaria Teresa Miras-Portugal, Madrid, SpainChrista Müller, Bonn, GermanyJoseph T Neary, Miami, USAYasunobe Okada, Okazaki, Japan
Jesus Pintor, Madrid, SpainAlex Ribeiro, Lisbon, PortugalMichael W Salter, Toronto, CanadaJana Sawynok, Halifax, CanadaAna Sebastião, Lisbon, PortugalEugene Silinsky, Chicago, USAMichail Sitkovsky, Bethesda, USABeata Sperlagh, Budapest, HungaryRandy Sprague, St. Louis, USAAnnmarie Surprenant, Sheffield, UKAlex Verkhratsky, Manchester, UKMark Voigt, St. Louis, USACinzia Volonte, Rome, ItalyGary Weisman, Missouri, USABen Yerxa, North Carolina, USA
Purinergic SignallingEditor-in-chief: Geoffrey Burnstock, London, UK
8787
Purinoceptors and Fast Purinergic Transmission at Neuromuscular Junctions and Synapses
Prof. Geoffrey Burnstock
30The screen versions of these slides have full details of copyright and acknowledgements
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