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. 2005 Aug;25(5):819–832. doi: 10.1007/s10571-005-4936-8

Co-activation of P2Y2 Receptor and TRPV Channel by ATP: Implications for ATP Induced Pain

Srihasam Lakshmi 1, Preeti G Joshi 1,✉
PMCID: PMC11529488  PMID: 16133936

Abstract

  1. Extracellular ATP is recognized as a peripheral modulator of pain. Activation of ionotropic P2X receptors in sensory neurons has been implicated in induction of pain, whereas metabotropic P2Y receptors in potentiation of pain induced by chemical or physical stimuli via capsaicin sensitive TRPV1 channel. Here we report that P2Y2 receptor activation by ATP can activate the TRPV1 channel in absence of any other stimuli.

  2. ATP-induced Ca2 + signaling was studied in Neuro2a cells. ATP evoked release of intracellular Ca2 + from ER and Ca2 + influx through a fast inactivating channel. The Ca2 + response was induced by P2Y receptor agonists in the order of potency ATP ≥ UTP ≥ ATPγ S > ADP and was inhibited by suramin and PPADS. The P2X receptor agonist α β methyl ATP was ineffective.

  3. The Ca2 + influx was blocked by ruthenium red, an inhibitor of TRPV1 channel. Capsaicin, the most potent activator of the TRPV1 channel, evoked a fast inactivating Ca2 + transient suggesting the presence of endogenous TRPV1 channels in Neuro2a cells. NMS and PDBu, repressors of IP3 formation, drastically inhibited both the components of Ca2 + response.

  4. Our data show co-activation of the P2Y2 receptor and capsaicin sensitive TRPV1 channel by ATP. Such functional interaction between endogenous P2Y2 receptor and TRPV1 channels could explain the ATP-induced pain.

Keywords: P2Y2 receptor, TRPV channel, capsaicin receptor, extracellular ATP, nociception, Neuro2a cells, intracellular Ca2 +, Fura-2

Abbreviations:

ADP

adenosine 5′-diphosphate

AMP

adenosine 5′-monophosphate

ATP

adenosine 5′-triphosphate

ATPγS

adenosine 5′-[γ -thio]triphosphate

αβ methyl ATP

α,β-methylene adenosine 5′-triphosphate

2 Me-S-ATP

2(methyl thio) adenosine 5′-triphosphate

CCE

capacitative calcium entry

CPA

cyclopiazonic acid

EGTA

ethylene glycol-bis (2-aminoethylether)-N,N,N′,N′-tetraacetic acid

GTP

guanosine 5′-triphoshate

IP3

inositol 1,4,5-triphosphate

NMS

neomycin sulphate

PDBu

phorbol 12,13-dibutyrate

PPADS

pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid)

PIP2

phosphoinositol-4,5-bisphosphate

PKC

protein kinase C

PLC

phosholipase C

PTx

pertussis toxin

SOC

store-operated calcium entry

TRPV

transient receptor potential channel, subfamily V

TRPC

transient receptor potential channel, subfamily C

UDP

uridine 5′-diphoshate

UTP

uridine 5′-triphoshate

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