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PMID: 15767570 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Receptor-induced depletion of phosphatidylinositol 4,5-bisphosphate inhibits inwardly rectifying K+ channels in a receptor-specific manner.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 102 ·No. 12 ·2005-03-22 ·Pages 4643-8

Cho H, Lee D, Lee SH, Ho WK

Abstract

Phosphatidylionsitol 4,5-bisphosphate (PIP(2)), a substrate of phospholipase C, has recently been recognized to regulate membrane-associated proteins and act as a signal molecule in phospholipase C-linked Gq-coupled receptor (GqPCR) pathways. However, it is not known whether PIP(2) depletion induced by GqPCRs can act as receptor-specific signals in native cells. We investigated this issue in cardiomyocytes where PIP(2)-dependent ion channels, G protein-gated inwardly rectifying K(+) (GIRK) and inwardly rectifying background K(+) (IRK) channels, and various GqPCRs are present. The GIRK current was recorded by using the patch-clamp technique during the application of 10 microM acetylcholine. The extent of receptor-mediated inhibition was estimated as the current decrease over 4 min while taking the GIRK current (I(GIRK)) value during a previous stimulation as the control. Each GqPCR agonist inhibited I(GIRK) with different potencies and kinetics. The extents of inhibition induced by phenylephrine, angiotensin II, endothelin-1, prostaglandin F2alpha, and bradykinin at supramaximal concentrations were (mean +/- SE) 32.1 +/- 0.6%, 21.9 +/- 1.4%, 86.4 +/- 1.6%, 63.7 +/- 4.9%, and 5.7 +/- 1.9%, respectively. GqPCR-induced inhibitions of I(GIRK) were not affected by protein kinase C inhibitor (calphostin C) but potentiated and became irreversible when the replenishment of PIP(2) was blocked by wortmannin (phosphatidylinositol kinase inhibitor). Loading the cells with PIP(2) significantly reduced endothelin-1 and prostaglandin F2alpha-induced inhibition of I(GIRK). On the contrary, GqPCR-mediated inhibitions of inwardly rectifying background K(+) currents were observed only when GqPCR agonists were applied with wortmannin, and the effects were not parallel with those on I(GIRK). These results indicate that GqPCR-induced inhibition of ion channels by means of PIP(2) depletion occurs in a receptor-specific manner.

MeSH Terms
Acetylcholine/pharmacology Androstadienes/pharmacology Angiotensin II/pharmacology Animals Bradykinin/pharmacology Dinoprost/pharmacology Endothelin-1/pharmacology G Protein-Coupled Inwardly-Rectifying Potassium Channels GTP-Binding Protein alpha Subunits, Gq-G11/drug effects,metabolism In Vitro Techniques Mice Myocytes, Cardiac/drug effects,metabolism Naphthalenes/pharmacology Patch-Clamp Techniques Phenylephrine/pharmacology Phosphatidylinositol 4,5-Diphosphate/metabolism Potassium Channels, Inwardly Rectifying/antagonists & inhibitors,drug effects,metabolism Wortmannin
Chemicals
Androstadienes Endothelin-1 G Protein-Coupled Inwardly-Rectifying Potassium Channels Naphthalenes Phosphatidylinositol 4,5-Diphosphate Potassium Channels, Inwardly Rectifying Angiotensin II Phenylephrine Dinoprost GTP-Binding Protein alpha Subunits, Gq-G11 calphostin C Acetylcholine Bradykinin Wortmannin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Cho Hana
National Research Laboratory for Cell Physiology, Department of Physiology, Seoul National University College of Medicine, 28 Yonkeun-Dong, Chongno-Ku, Seoul 110-799, Korea.
Lee Doyun
Lee Suk Ho
Ho Won-Kyung
References (50)
50 references, click to expand
  1. Do phosphatidylinositides modulate vertebrate phototransduction?
    J Neurosci. 2000 Apr 15;20(8):2792-9 PMID: 10751430
  2. Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel by means of phosphatidylinositol 4,5-bisphosphate metabolism.
    Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15292-7 PMID: 10611378
  3. Characterization of G-protein signaling in ventricular myocytes from the adult mouse heart: differences from the rat.
    J Mol Cell Cardiol. 2000 Jul;32(7):1211-21 PMID: 10860764
  4. Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization.
    Nat Cell Biol. 2000 Aug;2(8):507-14 PMID: 10934471
  5. TrkB activation by brain-derived neurotrophic factor inhibits the G protein-gated inward rectifier Kir3 by tyrosine phosphorylation of the channel.
    J Biol Chem. 2000 Aug 18;275(33):25082-8 PMID: 10833508
  6. Intracellular delivery of phosphoinositides and inositol phosphates using polyamine carriers.
    Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11286-91 PMID: 11005844
  7. Phosphatidylinositol 4,5-bisphosphate is acting as a signal molecule in alpha(1)-adrenergic pathway via the modulation of acetylcholine-activated K(+) channels in mouse atrial myocytes.
    J Biol Chem. 2001 Jan 5;276(1):159-64 PMID: 11029461
  8. Regulation of a G protein-gated inwardly rectifying K+ channel by a Ca(2+)-independent protein kinase C.
    J Physiol. 2001 Jul 15;534(Pt. 2):367-79 PMID: 11454957
  9. Overexpression of beta 1 and beta 2 adrenergic receptors in rat atrial myocytes. Differential coupling to G protein-gated inward rectifier K(+) channels via G(s) and G(i)/o.
    J Biol Chem. 2001 Oct 5;276(40):37347-54 PMID: 11495921
  10. Inhibition of acetylcholine-activated K(+) current by chelerythrine and bisindolylmaleimide I in atrial myocytes from mice.
    Eur J Pharmacol. 2001 Jul 27;424(3):173-8 PMID: 11672559
  11. Gi Irks GIRKs.
    Neuron. 2002 Jan 3;33(1):6-8 PMID: 11779473
  12. Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies.
    Neuron. 2002 Jun 13;34(6):933-44 PMID: 12086641
  13. Acetylcholine-induced phosphatidylinositol 4,5-bisphosphate depletion does not cause short-term desensitization of G protein-gated inwardly rectifying K+ current in mouse atrial myocytes.
    J Biol Chem. 2002 Aug 2;277(31):27742-7 PMID: 12019267
  14. Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis.
    Neuron. 2002 Aug 1;35(3):507-20 PMID: 12165472
  15. PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents.
    Neuron. 2003 Mar 27;37(6):963-75 PMID: 12670425
  16. Coupling to Gs and G(q/11) of histamine H2 receptors heterologously expressed in adult rat atrial myocytes.
    Biochim Biophys Acta. 2003 Sep 23;1642(1-2):67-77 PMID: 12972295
  17. Molecular basis for the inhibition of G protein-coupled inward rectifier K(+) channels by protein kinase C.
    Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):1087-92 PMID: 14732702
  18. Mechanosensitivity of GIRK channels is mediated by protein kinase C-dependent channel-phosphatidylinositol 4,5-bisphosphate interaction.
    J Biol Chem. 2004 Feb 20;279(8):7037-47 PMID: 14660621
  19. Fade of cardiac responses during tonic vagal stimulation.
    Am J Physiol. 1982 Aug;243(2):H219-25 PMID: 7114232
  20. Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2.
    Science. 1996 Aug 16;273(5277):956-9 PMID: 8688080
  21. Regulatory mechanisms that modulate signalling by G-protein-coupled receptors.
    Biochem J. 1997 Feb 15;322 ( Pt 1):1-18 PMID: 9078236
  22. Positive and negative coupling of the metabotropic glutamate receptors to a G protein-activated K+ channel, GIRK, in Xenopus oocytes.
    J Gen Physiol. 1997 Apr;109(4):477-90 PMID: 9101406
  23. Regulation of phospholipases C and D in rat ventricular myocytes: stimulation by endothelin-1, bradykinin and phenylephrine.
    J Mol Cell Cardiol. 1997 Jun;29(6):1593-604 PMID: 9220345
  24. Left ventricular stretch stimulates angiotensin II--mediated phosphatidylinositol hydrolysis and protein kinase C epsilon isoform translocation in adult guinea pig hearts.
    Circ Res. 1997 Nov;81(5):643-50 PMID: 9351436
  25. Dual effects of endothelins on the muscarinic K+ current in guinea pig atrial cells.
    Am J Physiol. 1997 Oct;273(4 Pt 2):H1745-53 PMID: 9362239
  26. Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice.
    Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13311-6 PMID: 9371842
  27. ATP-dependent desensitization of the muscarinic K+ channel in rat atrial cells.
    J Physiol. 1997 Nov 15;505 ( Pt 1):77-93 PMID: 9409473
  28. Activation of the atrial KACh channel by the betagamma subunits of G proteins or intracellular Na+ ions depends on the presence of phosphatidylinositol phosphates.
    Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1307-12 PMID: 9448327
  29. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma.
    Nature. 1998 Feb 19;391(6669):803-6 PMID: 9486652
  30. Differential regulation of muscarinic acetylcholine receptor-sensitive polyphosphoinositide pools and consequences for signaling in human neuroblastoma cells.
    J Biol Chem. 1998 Feb 27;273(9):5037-46 PMID: 9478953
  31. Functional coupling of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate receptor.
    J Biol Chem. 1998 Jun 5;273(23):14067-70 PMID: 9603901
  32. Bradykinin inhibits M current via phospholipase C and Ca2+ release from IP3-sensitive Ca2+ stores in rat sympathetic neurons.
    Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):7151-6 PMID: 9618554
  33. Evidence that the nucleotide exchange and hydrolysis cycle of G proteins causes acute desensitization of G-protein gated inward rectifier K+ channels.
    Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11727-32 PMID: 9751733
  34. G-protein coupled receptor kinases as modulators of G-protein signalling.
    J Physiol. 1999 May 15;517 ( Pt 1):5-23 PMID: 10226145
  35. Muscarinic M1 receptors activate phosphoinositide turnover and Ca2+ mobilisation in rat sympathetic neurones, but this signalling pathway does not mediate M-current inhibition.
    J Physiol. 1999 Oct 1;520 Pt 1:101-11 PMID: 10517804
  36. Acetylcholine activation of single muscarinic K+ channels in isolated pacemaker cells of the mammalian heart.
    Nature. 1983 May 19-25;303(5914):250-3 PMID: 6302520
  37. GTP-binding proteins couple cardiac muscarinic receptors to a K channel.
    Nature. 1985 Oct 10-16;317(6037):536-8 PMID: 2413367
  38. Uncoupling of cardiac muscarinic and beta-adrenergic receptors from ion channels by a guanine nucleotide analogue.
    Nature. 1985 Oct 10-16;317(6037):538-40 PMID: 2413368
  39. Desensitization of the acetylcholine-induced increase of potassium conductance in rabbit cardiac Purkinje fibres.
    J Physiol. 1986 Feb;371:239-55 PMID: 2422349
  40. Acetylcholine activation of K+ channels in cell-free membrane of atrial cells.
    Am J Physiol. 1986 Sep;251(3 Pt 2):H681-4 PMID: 2428258
  41. A G protein couples serotonin and GABAB receptors to the same channels in hippocampus.
    Science. 1986 Dec 5;234(4781):1261-5 PMID: 2430334
  42. The fade of the response to acetylcholine at the rabbit isolated sino-atrial node.
    J Physiol. 1987 Dec;393:171-94 PMID: 3446796
  43. Muscarinic suppression of the M-current in the rat sympathetic ganglion is mediated by receptors of the M1-subtype.
    Br J Pharmacol. 1989 Oct;98(2):557-73 PMID: 2819334
  44. Activation of alpha 1-adrenoceptors modulates the inwardly rectifying potassium currents of mammalian atrial myocytes.
    Pflugers Arch. 1992 Aug;421(5):431-9 PMID: 1361052
  45. On the role of G protein activation and phosphorylation in desensitization to acetylcholine in guinea-pig atrial cells.
    J Physiol. 1993 May;464:649-79 PMID: 8229823
  46. Protein kinase C-mediated inhibition of an inward rectifier potassium channel by substance P in nucleus basalis neurons.
    Neuron. 1995 May;14(5):999-1008 PMID: 7538311
  47. Synergistic regulation of a neuronal chloride current by intracellular calcium and muscarinic receptor activation: a role for protein kinase C.
    Neuron. 1995 Sep;15(3):729-37 PMID: 7546751
  48. Wortmannin and its structural analogue demethoxyviridin inhibit stimulated phospholipase A2 activity in Swiss 3T3 cells. Wortmannin is not a specific inhibitor of phosphatidylinositol 3-kinase.
    J Biol Chem. 1995 Oct 27;270(43):25352-5 PMID: 7592698
  49. Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions.
    Nat Cell Biol. 1999 Jul;1(3):183-8 PMID: 10559906
  50. Two different signaling mechanisms involved in the excitation of rat sympathetic neurons by uridine nucleotides.
    Mol Pharmacol. 2000 Jun;57(6):1165-72 PMID: 10825387
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0408844102
Published
2005-03-22
Epub
2005-00-14
Pages
4643-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC555493
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0408844102 PMC Full Text View journal details
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