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P2Y receptor subtypes evoke different Ca2+ signals in cultured aortic smooth muscle cells

Sriram Govindan1, Colin W Taylor

  • 1Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.

Purinergic Signalling
|July 7, 2012
PubMed

Insights

Four P2Y receptor subtypes in aortic smooth muscle cells use common pathways for calcium (Ca2+) signaling. Differences in desensitization rates and receptor expression explain varied Ca2+ signal patterns, revealing key mechanisms in vascular smooth muscle function.

Area of Science:

  • Cellular Physiology
  • Vascular Biology
  • Receptor Pharmacology

Background:

  • Adenine and uridine nucleotides trigger calcium (Ca2+) signals in aortic smooth muscle cells through P2Y receptors.
  • The precise mechanisms behind the distinct Ca2+ signal patterns elicited by different P2Y receptor subtypes remain unclear.

Purpose of the Study:

  • To investigate the signaling pathways and mechanisms responsible for Ca2+ signal generation by four P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6) in cultured rat aortic smooth muscle cells.
  • To elucidate the factors contributing to the differential patterns of Ca2+ signaling observed among these receptor subtypes.

Main Methods:

  • Measurement of cytosolic Ca2+ signals in single cultured rat aortic smooth muscle cells using a fluorescent Ca2+ indicator.
  • Stimulation of cells with subtype-selective P2Y receptor agonists.
  • Pharmacological inhibition of key signaling molecules including phospholipase C, inositol 1,4,5-trisphosphate (IP3) receptors, ryanodine receptors, nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, and the Na+/Ca2+ exchanger.

Main Results:

  • All four P2Y receptor subtypes activated phospholipase C and released Ca2+ from intracellular stores via IP3 receptors, independent of ryanodine or NAADP receptors.
  • Sustained Ca2+ signals were mediated by store-operated Ca2+ entry, not the Na+/Ca2+ exchanger.
  • Homologous desensitization occurred upon activation of P2Y1, P2Y2, and P2Y6 receptors; P2Y2 activation also induced heterologous desensitization of other subtypes. Most cells expressed P2Y2 and at least two other subtypes.

Conclusions:

  • Four P2Y receptor subtypes in aortic smooth muscle cells utilize common intracellular (IP3 receptors) and Ca2+ entry (store-operated Ca2+ entry) pathways for Ca2+ signaling.
  • Differential rates of homologous desensitization and varying receptor expression levels are key determinants of the distinct Ca2+ signal patterns evoked by each P2Y receptor subtype.

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