Inhibition of potassium and calcium currents in neurones by molecularly-defined P2Y receptors

https://doi.org/10.1016/S0165-1838(00)00150-8Get rights and content

Abstract

Messenger RNAs and cDNAs for individual cloned P2Y1, P2Y2 and P2Y6 nucleotide receptors have been expressed by micro-injection into dissociated rat superior cervical sympathetic neurones and the effects of stimulting the expressed receptors on voltage-activated N-type Ca2+ currents and M-type K+ currents recorded. Both currents were reduced by stimulating all three receptors, with the following mean IC50 values: P2Y1 (agonist: ADP) – IK(M) 6.9 nM, ICa 8.2 nM; P2Y2 (agonist: UTP) – IK(M) 1.5 μM, ICa 0.5 μM; P2Y6 (agonist: UDP) – IK(M) 30 nM, ICa 5.9 nM. Inhibition of IK(M) was voltage-independent and insensitive to Pertussis toxin; inhibition of ICa showed both voltage-sensitive and insensitive, and Pertussis toxin-sensitive and insensitive components. It is concluded that these P2Y receptors can couple to more than one G protein and thereby modulate more than one ion channel. It is suggested that these effects on KM and CaN channels may induce both postsynaptic excitory and presynaptic inhibitory responses.

Section snippets

Acknowledgements

This work was supported by grants from the Wellcome Trust.

References (40)

  • S. Boehm

    Selective inhibition of M-type potassium channels in rat sympathetic neurons by uridine nucleotide preferring receptors

    Br. J. Pharmacol.

    (1998)
  • J.-M. Boeynaems et al.

    Nucleotide receptors coupling to the phospholipase C signaling pathway

  • D.A. Brown et al.

    Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone

    Nature

    (1980)
  • M.P. Caulfield et al.

    Muscarinic M-current inhibition via Gαq/11 and α-adrenoceptor inhibition of Ca2+ current via Gαo in rat sympathetic neurones

    J. Physiol.

    (1994)
  • R. Cloues et al.

    Zn2+ potentiates ATP-activated currents in rat sympathetic neurons

    Pflugers Arch.

    (1993)
  • G.P. Connolly et al.

    Structure–activity relationships of a pyrimidine receptor in the rat isolated superior cervical ganglion

    Br. J. Pharmacol.

    (1995)
  • H. Cruzblanca et al.

    Bradykinin inhibits M current via phospholipase C and Ca2+ release from IP3-sensitive stores in rat sympathetic neurons

    Proc. Natl. Acad. Sci. USA

    (1998)
  • P. Delmas et al.

    On the role of endogenous G-protein βγ subunits in N-type Ca2+ current inhibition by neurotransmitters in rat sympathetic neurones

    J. Physiol.

    (1998)
  • P. Delmas et al.

    G-proteins and G-protein subunits mediating cholinergic inhibition of N-type calcium currents

    Eur. J. Neurosci.

    (1998)
  • A.K. Filippov et al.

    Activation of nucleotide receptors inhibits high-threshold calcium currents in NG108-15 neuronal hybrid cells

    Eur. J. Neurosci.

    (1996)
  • Cited by (41)

    • The role of P2Y<inf>1</inf> receptor signaling in central respiratory control

      2016, Respiratory Physiology and Neurobiology
      Citation Excerpt :

      P2Y1 receptors inhibit N-type Ca2+ channels in superior cervical ganglion neurons via the Gαq pathway, but the inhibition is dependent on the βγ- rather than the αq subunit (Herlitze et al., 1996; Ikeda, 1996; Brown et al., 2000; Filippov et al., 2000). Unconventional actions of P2Y1 receptors in NTS neurons through the Gαi pathway produce a βγ-dependent inhibition of N-, P/Q- and L-type Ca2+ channels (Brown et al., 2000; Filippov et al., 2000; Aoki et al., 2004). N- and L-type Ca2+ currents are present in all classes of respiratory neurons while P/Q-type Ca2+ currents are limited to pre-inspiratory neurons and a subset of inspiratory neurons (Onimaru et al., 1996).

    • P2Y purinergic receptor-regulated insulin secretion is mediated by a cAMP/Epac/Kv channel pathway

      2015, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      The data are in line with previous findings performed in rat adult ventricle, where Epac activator has been found to prolong action potential duration by decreasing potassium current [19]. In neurons, inhibition of potassium current by stimulating P2YR has also been reported [20]. We thus believe that Kv channel may be the important contributor that mediates P2YR-modulated insulin secretion, which is confirmed by our experiment in insulin secretion assays.

    • Nucleotides control the excitability of sensory neurons via two P2Y receptors and a bifurcated signaling cascade

      2011, Pain
      Citation Excerpt :

      However, we found no evidence for an induction of chloride currents by any of the nucleotides tested (not shown). The inhibition of KV7 channels by both P2Y1 and P2Y2 has also been observed with receptors heterologously expressed in sympathetic neurons [9]. TRPV1 channels mediate acute and chronic pain [22], and ADP as well as 2-thio-UTP enhanced currents through these receptors; this effect of ADP, but not that of 2-thio-UTP, was again antagonized by MRS 2179.

    • ATP in central respiratory control: A three-part signaling system

      2008, Respiratory Physiology and Neurobiology
    • Inhibitory purinergic P2 receptor characterisation in rat distal colon

      2007, Neuropharmacology
      Citation Excerpt :

      MRS2179 also reduced the αβmeATP-induced responses in a concentration range of 1–30 μM, indicating that the selectivity window of this antagonist is limited to concentrations up to 0.3 μM. Correspondingly, Brown et al. (2000a,b) reported MRS2179 to inhibit purinergic responses at cloned rat P2X1 receptors with an IC50 value of 1.15 μM. P2Y1 receptor-induced relaxations are known to involve PLC activation and IP3 generation causing highly directional and localised Ca2+ transients (Ca2+-puffs) from the sarcoplasmic reticulum (SR) that will subsequently initiate an increase in K+ efflux by activation of apamin-sensitive small conductance Ca2+-sensitive K+ (SK) channels, leading to hyperpolarisation and relaxation (Bayguinov et al., 2000; Van Crombruggen and Lefebvre, 2004).

    View all citing articles on Scopus
    View full text