ATP inhibits Ins(1,4,5)P3-evoked Ca2+ release in smooth muscle via P2Y1 receptors

Debbi MacMillan, Charles Kennedy, John McCarron

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Adenosine 5′-triphosphate (ATP) mediates a variety of biological functions following nerve-evoked release, via activation of either G protein-coupled P2Y- or ligand-gated P2X-receptors. In smooth muscle, ATP, acting via P2Y receptors (P2YR), may act as an inhibitory neurotransmitter. The underlying mechanism(s) remain unclear, but have been proposed to involve the production of inositol 1,4,5-trisphosphate (IP3) by phospholipase C (PLC), to evoke Ca2+ release from the internal store and stimulation of Ca2+-activated potassium (KCa) channels to cause membrane hyperpolarization. This mechanism requires Ca2+ release from the store. However, in the present study, ATP evoked transient Ca2+ increases in only ∼10% of voltage-clamped single smooth muscle cells. These results do not support activation of KCa as the major mechanism underlying inhibition of smooth muscle activity. Interestingly, ATP inhibited IP3-evoked Ca2+ release in cells that did not show a Ca2+ rise in response to purinergic activation. The reduction in IP3-evoked Ca2+ release was not mimicked by adenosine and therefore, cannot be explained by hydrolysis of ATP to adenosine. The reduction in IP3-evoked Ca2+ release was, however, also observed with its primary metabolite, ADP, and blocked by the P2Y1R antagonist, MRS2179, and the G protein inhibitor, GDPβS, but not by PLC inhibition. The present study demonstrates a novel inhibitory effect of P2Y1R activation on IP3-evoked Ca2+ release, such that purinergic stimulation acts to prevent IP3-mediated increases in excitability in smooth muscle and promote relaxation.
LanguageEnglish
Pages5151-5158
Number of pages8
JournalJournal of Cell Science
Volume125
Issue number21
Early online date16 Aug 2012
DOIs
Publication statusPublished - 1 Nov 2012

Fingerprint

Purinergic P2Y1 Receptors
Smooth Muscle
Adenosine Triphosphate
Type C Phospholipases
GTP-Binding Proteins
Adenosine
Muscle Relaxation
Inositol 1,4,5-Trisphosphate
Potassium Channels
Adenosine Diphosphate
Smooth Muscle Myocytes
Neurotransmitter Agents
Hydrolysis
Ligands
Membranes

Keywords

  • ATP
  • smooth muscle
  • IP3
  • P2Y1 receptors

Cite this

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title = "ATP inhibits Ins(1,4,5)P3-evoked Ca2+ release in smooth muscle via P2Y1 receptors",
abstract = "Adenosine 5′-triphosphate (ATP) mediates a variety of biological functions following nerve-evoked release, via activation of either G protein-coupled P2Y- or ligand-gated P2X-receptors. In smooth muscle, ATP, acting via P2Y receptors (P2YR), may act as an inhibitory neurotransmitter. The underlying mechanism(s) remain unclear, but have been proposed to involve the production of inositol 1,4,5-trisphosphate (IP3) by phospholipase C (PLC), to evoke Ca2+ release from the internal store and stimulation of Ca2+-activated potassium (KCa) channels to cause membrane hyperpolarization. This mechanism requires Ca2+ release from the store. However, in the present study, ATP evoked transient Ca2+ increases in only ∼10{\%} of voltage-clamped single smooth muscle cells. These results do not support activation of KCa as the major mechanism underlying inhibition of smooth muscle activity. Interestingly, ATP inhibited IP3-evoked Ca2+ release in cells that did not show a Ca2+ rise in response to purinergic activation. The reduction in IP3-evoked Ca2+ release was not mimicked by adenosine and therefore, cannot be explained by hydrolysis of ATP to adenosine. The reduction in IP3-evoked Ca2+ release was, however, also observed with its primary metabolite, ADP, and blocked by the P2Y1R antagonist, MRS2179, and the G protein inhibitor, GDPβS, but not by PLC inhibition. The present study demonstrates a novel inhibitory effect of P2Y1R activation on IP3-evoked Ca2+ release, such that purinergic stimulation acts to prevent IP3-mediated increases in excitability in smooth muscle and promote relaxation.",
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ATP inhibits Ins(1,4,5)P3-evoked Ca2+ release in smooth muscle via P2Y1 receptors. / MacMillan, Debbi; Kennedy, Charles; McCarron, John.

In: Journal of Cell Science, Vol. 125, No. 21, 01.11.2012, p. 5151-5158.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ATP inhibits Ins(1,4,5)P3-evoked Ca2+ release in smooth muscle via P2Y1 receptors

AU - MacMillan, Debbi

AU - Kennedy, Charles

AU - McCarron, John

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N2 - Adenosine 5′-triphosphate (ATP) mediates a variety of biological functions following nerve-evoked release, via activation of either G protein-coupled P2Y- or ligand-gated P2X-receptors. In smooth muscle, ATP, acting via P2Y receptors (P2YR), may act as an inhibitory neurotransmitter. The underlying mechanism(s) remain unclear, but have been proposed to involve the production of inositol 1,4,5-trisphosphate (IP3) by phospholipase C (PLC), to evoke Ca2+ release from the internal store and stimulation of Ca2+-activated potassium (KCa) channels to cause membrane hyperpolarization. This mechanism requires Ca2+ release from the store. However, in the present study, ATP evoked transient Ca2+ increases in only ∼10% of voltage-clamped single smooth muscle cells. These results do not support activation of KCa as the major mechanism underlying inhibition of smooth muscle activity. Interestingly, ATP inhibited IP3-evoked Ca2+ release in cells that did not show a Ca2+ rise in response to purinergic activation. The reduction in IP3-evoked Ca2+ release was not mimicked by adenosine and therefore, cannot be explained by hydrolysis of ATP to adenosine. The reduction in IP3-evoked Ca2+ release was, however, also observed with its primary metabolite, ADP, and blocked by the P2Y1R antagonist, MRS2179, and the G protein inhibitor, GDPβS, but not by PLC inhibition. The present study demonstrates a novel inhibitory effect of P2Y1R activation on IP3-evoked Ca2+ release, such that purinergic stimulation acts to prevent IP3-mediated increases in excitability in smooth muscle and promote relaxation.

AB - Adenosine 5′-triphosphate (ATP) mediates a variety of biological functions following nerve-evoked release, via activation of either G protein-coupled P2Y- or ligand-gated P2X-receptors. In smooth muscle, ATP, acting via P2Y receptors (P2YR), may act as an inhibitory neurotransmitter. The underlying mechanism(s) remain unclear, but have been proposed to involve the production of inositol 1,4,5-trisphosphate (IP3) by phospholipase C (PLC), to evoke Ca2+ release from the internal store and stimulation of Ca2+-activated potassium (KCa) channels to cause membrane hyperpolarization. This mechanism requires Ca2+ release from the store. However, in the present study, ATP evoked transient Ca2+ increases in only ∼10% of voltage-clamped single smooth muscle cells. These results do not support activation of KCa as the major mechanism underlying inhibition of smooth muscle activity. Interestingly, ATP inhibited IP3-evoked Ca2+ release in cells that did not show a Ca2+ rise in response to purinergic activation. The reduction in IP3-evoked Ca2+ release was not mimicked by adenosine and therefore, cannot be explained by hydrolysis of ATP to adenosine. The reduction in IP3-evoked Ca2+ release was, however, also observed with its primary metabolite, ADP, and blocked by the P2Y1R antagonist, MRS2179, and the G protein inhibitor, GDPβS, but not by PLC inhibition. The present study demonstrates a novel inhibitory effect of P2Y1R activation on IP3-evoked Ca2+ release, such that purinergic stimulation acts to prevent IP3-mediated increases in excitability in smooth muscle and promote relaxation.

KW - ATP

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