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A Ca²⁺-dependent chloride current and Ca²⁺ influx via Ca(v)1.2 ion channels play major roles in P2Y receptor-mediated

Callum Mitchell1, Nawazish-i-Husain Syed, Alison M Gurney

  • 1Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

British Journal of Pharmacology
|February 11, 2012
PubMed
Abstract

Insights

Calcium-dependent chloride current and calcium influx through Ca(v)1.2 channels equally contribute to UTP and UDP-induced contractions in rat pulmonary arteries. ATP also activates these pathways, but with greater extracellular calcium dependence, likely via P2X1 receptors.

Area of Science:

  • Physiology
  • Pharmacology
  • Vascular Biology

Background:

  • Nucleotides like ATP, UTP, and UDP activate P2X and P2Y receptors in smooth muscle.
  • These receptors play a role in constricting rat intrapulmonary arteries.
  • The specific signaling pathways involved in these contractions are not well understood.

Purpose of the Study:

  • To investigate the roles of calcium-dependent chloride ion current (I(Cl,Ca)), Ca(v)1.2 ion channels, and calcium influx in nucleotide-induced pulmonary artery contractions.
  • To elucidate the signaling mechanisms underlying P2 receptor-mediated vasoconstriction.

Main Methods:

  • Isometric tension recordings from endothelium-denuded rat intrapulmonary artery rings using a wire myograph.
  • Application of nucleotide agonists (ATP, UTP, UDP) and specific channel blockers (niflumic acid, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, nifedipine).
  • Experiments conducted in normal and calcium-free buffer conditions.

Main Results:

  • I(Cl,Ca) blockers and the Ca(v)1.2 channel blocker nifedipine significantly reduced UTP and UDP-evoked contractions by approximately 45-50%.
  • Calcium-free buffer inhibited responses by about 70%, indicating a substantial role for calcium influx.
  • ATP-induced contractions showed a greater dependence on extracellular calcium and rapid reversal, suggesting additional P2X1 receptor involvement.

Conclusions:

  • Both I(Cl,Ca) and Ca²⁺ influx via Ca(v)1.2 channels are crucial and equally contribute to UTP and UDP-induced contractions via P2Y receptors.
  • ATP also engages these pathways via P2Y receptors, with additional calcium influx likely through P2X1 receptors.
  • Rapid desensitization of certain P2 receptor subtypes may explain the transient nature of ATP-evoked contractions, highlighting multiple signaling mechanisms in P2 receptor-mediated pulmonary vasoconstriction.

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