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Modulation of cyclic nucleotide-regulated HCN channels by PIP2 and receptors coupled to phospholipase C

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Abstract

Recent results indicate that phosphoinositides, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), directly enhance the opening of hyperpolarization-activated, cyclic nucleotide-regulated (HCN) channels by shifting their activation gating to more positive voltages. This contrasts with the action of phosphoinositides to inhibit the opening of the related cyclic nucleotide-gated (CNG) channels involved in sensory signaling. We both review previous studies and present new experiments that investigate whether HCN channels may be regulated by dynamic changes in PI(4,5)P2 levels caused by the receptor-mediated activation of phospholipase C (PLC). We coexpressed HCN1 or HCN2 channels in Xenopus oocytes with the PLC-coupled bradykinin BK2 receptor, the muscarinic M1 receptor, or the TrkA receptor. Activation of all three receptors produced a positive shift in HCN channel voltage gating, the opposite of the effect expected for PI(4,5)P2 depletion. This action was not caused by alterations in cAMP as the effect was preserved in HCN mutant channels that fail to bind cAMP. The receptor effects were mediated by PLC activity, but did not depend on signaling through the downstream products of PI(4,5)P2 hydrolysis: IP3 or diacylglycerol (DAG). Importantly, the modulatory effects on gating were blocked by inhibitors of phosphatidylinositol (PI) kinases, suggesting a role for increased PI(4,5)P2 synthesis. Finally, we found that bradykinin exerted a similar PI kinase-dependent effect on the gating of native HCN channels in cardiac sinoatrial node cells, suggesting that this pathway may represent a novel, physiologically relevant mechanism for enhancing HCN channel function.

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References

  1. Arcaro A, Wymann MP (1993) Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem J 296(Pt 2):297–301

    PubMed  CAS  Google Scholar 

  2. Arinsburg SS, Cohen IS, Yu HG (2006) Constitutively active Src tyrosine kinase changes gating of HCN4 channels through direct binding to the channel proteins. J Cardiovasc Pharmacol 47:578–586

    Article  PubMed  CAS  Google Scholar 

  3. Balla A, Balla T (2006) Phosphatidylinositol 4-kinases: old enzymes with emerging functions. Trends Cell Biol 16:351–361

    Article  PubMed  CAS  Google Scholar 

  4. Barbuti A, Gravante B, Riolfo M, Milanesi R, Terragni B, DiFrancesco D (2004) Localization of pacemaker channels in lipid rafts regulates channel kinetics. Circ Res 94:1325–1331

    Article  PubMed  CAS  Google Scholar 

  5. Barbuti A, Terragni B, Brioschi C, Difrancesco D (2007) Localization of f-channels to caveolae mediates specific beta(2)-adrenergic receptor modulation of rate in sinoatrial myocytes. J Mol Cell Cardiol 42:71–78

    Article  PubMed  CAS  Google Scholar 

  6. Baron CB, Pompeo J, Blackman D, Coburn RF (1993) Common phosphatidylinositol 4,5-bisphosphate pools are involved in carbachol and serotonin activation of tracheal smooth muscle. J Pharmacol Exp Ther 266:8–15

    PubMed  CAS  Google Scholar 

  7. Berridge MJ (1984) Inositol trisphosphate and diacylglycerol as second messengers. Biochem J 220:345–360

    PubMed  CAS  Google Scholar 

  8. Brose N, Betz A, Wegmeyer H (2004) Divergent and convergent signaling by the diacylglycerol second messenger pathway in mammals. Curr Opin Neurobiol 14:328–340

    Article  PubMed  CAS  Google Scholar 

  9. Cathala L, Paupardin-Tritsch D (1997) Neurotensin inhibition of the hyperpolarization-activated cation current (Ih) in the rat substantia nigra pars compacta implicates the protein kinase C pathway. J Physiol 503(Pt 1):87–97

    Article  PubMed  CAS  Google Scholar 

  10. Chang F, Cohen IS, DiFrancesco D, Rosen MR, Tromba C (1991) Effects of protein kinase inhibitors on canine Purkinje fibre pacemaker depolarization and the pacemaker current if. J Physiol 440:367–384

    PubMed  CAS  Google Scholar 

  11. Chen S, Wang J, Siegelbaum SA (2001) Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J Gen Physiol 117:491–504

    Article  PubMed  CAS  Google Scholar 

  12. Chen TY, Yau KW (1994) Direct modulation by Ca(2+)-calmodulin of cyclic nucleotide-activated channel of rat olfactory receptor neurons. Nature 368:545–548

    Article  PubMed  CAS  Google Scholar 

  13. Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962

    Article  PubMed  CAS  Google Scholar 

  14. Craven KB, Zagotta WN (2006) CNG and HCN channels: two peas, one pod. Annu Rev Physiol 68:375–401

    Article  PubMed  CAS  Google Scholar 

  15. DiFrancesco D, Ferroni A, Mazzanti M, Tromba C (1986) Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node. J Physiol 377:61–88

    PubMed  CAS  Google Scholar 

  16. Egli M, Berger T, Imboden H (2002) Angiotensin II influences the hyperpolarization-activated current Ih in neurones of the rat paraventricular nucleus. Neurosci Lett 330:53–56

    Article  PubMed  CAS  Google Scholar 

  17. Fogle KJ, Lyashchenko AK, Turbendian HK, Tibbs GR (2007) HCN pacemaker channel activation is controlled by acidic lipids downstream of diacylglycerol kinase and phospholipase A2. J Neurosci 27:2802–2814

    Article  PubMed  CAS  Google Scholar 

  18. Furuichi T, Yoshikawa S, Miyawaki A, Wada K, Maeda N, Mikoshiba K (1989) Primary structure and functional expression of the inositol 1,4,5-trisphosphate-binding protein P400. Nature 342:32–38

    Article  PubMed  CAS  Google Scholar 

  19. Gamper N, Reznikov V, Yamada Y, Yang J, Shapiro MS (2004) Phosphatidylinositol [correction] 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels. J Neurosci 24:10980–10992

    Article  PubMed  CAS  Google Scholar 

  20. Gerber U, Gee CE, Benquet P (2007) Metabotropic glutamate receptors: intracellular signaling pathways. Curr Opin Pharmacol 7:56–61

    Article  PubMed  CAS  Google Scholar 

  21. Gomez-Hernandez JM, Stuhmer W, Parekh AB (1997) Calcium dependence and distribution of calcium-activated chloride channels in Xenopus oocytes. J Physiol 502(Pt 3):569–574

    Article  PubMed  CAS  Google Scholar 

  22. Goulding EH, Ngai J, Kramer RH, Colicos S, Axel R, Siegelbaum SA, Chess A (1992) Molecular cloning and single-channel properties of the cyclic nucleotide-gated channel from catfish olfactory neurons. Neuron 8:45–58

    Article  PubMed  CAS  Google Scholar 

  23. Hagiwara N, Irisawa H (1989) Modulation by intracellular Ca2+ of the hyperpolarization-activated inward current in rabbit single sino-atrial node cells. J Physiol 409:121–141

    PubMed  CAS  Google Scholar 

  24. Hendricks KB, Wang BQ, Schnieders EA, Thorner J (1999) Yeast homologue of neuronal frequenin is a regulator of phosphatidylinositol-4-OH kinase. Nat Cell Biol 1:234–241

    Article  PubMed  CAS  Google Scholar 

  25. Hilgemann DW, Ball R (1996) Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2. Science 273:956–959

    Article  PubMed  CAS  Google Scholar 

  26. Hilgemann DW, Feng S, Nasuhoglu C (2001) The complex and intriguing lives of PIP2 with ion channels and transporters. Sci Signal Transduct Knowl Environ 2001:RE19

    CAS  Google Scholar 

  27. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G (1999) Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397:259–263

    Article  PubMed  CAS  Google Scholar 

  28. Honda A, Nogami M, Yokozeki T, Yamazaki M, Nakamura H, Watanabe H, Kawamoto K, Nakayama K, Morris AJ, Frohman MA, Kanaho Y (1999) Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the small G protein ARF6 in membrane ruffle formation. Cell 99:521–532

    Article  PubMed  CAS  Google Scholar 

  29. Hughes S, Marsh SJ, Tinker A, Brown DA (2007) PIP2-dependent inhibition of M-type (Kv7.2/7.3) potassium channels: direct on-line assessment of PIP2 depletion by Gq-coupled receptors in single living neurons. Pflugers Arch (in press)

  30. Jafri MS, Weinreich D (1998) Substance P regulates Ih via a NK-1 receptor in vagal sensory neurons of the ferret. J Neurophysiol 79:769–777

    PubMed  CAS  Google Scholar 

  31. Kiss Z, Farkas T (1975) The effect of isoproterenol on the metabolism of phosphatidylinositol by rat heart in vitro. Biochem Pharmacol 24:999–1002

    Article  PubMed  CAS  Google Scholar 

  32. Kobrinsky E, Mirshahi T, Zhang H, Jin T, Logothetis DE (2000) Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization. Nat Cell Biol 2:507–514

    Article  PubMed  CAS  Google Scholar 

  33. Kroeze WK, Kristiansen K, Roth BL (2002) Molecular biology of serotonin receptors structure and function at the molecular level. Curr Top Med Chem 2:507–528

    Article  PubMed  CAS  Google Scholar 

  34. Lambert S, Vind-Kezunovic D, Karvinen S, Gniadecki R (2006) Ligand-independent activation of the EGFR by lipid raft disruption. J Invest Dermatol 126:954–962

    Article  PubMed  CAS  Google Scholar 

  35. Lassing I, Lindberg U (1990) Polyphosphoinositide synthesis in platelets stimulated with low concentrations of thrombin is enhanced before the activation of phospholipase C. FEBS Lett 262:231–233

    Article  PubMed  CAS  Google Scholar 

  36. Lei Q, Jones MB, Talley EM, Garrison JC, Bayliss DA (2003) Molecular mechanisms mediating inhibition of G protein-coupled inwardly rectifying K+ channels. Mol Cells 15:1–9

    PubMed  CAS  Google Scholar 

  37. Li SJ, Wang Y, Strahlendorf HK, Strahlendorf JC (1993) Serotonin alters an inwardly rectifying current (Ih) in rat cerebellar Purkinje cells under voltage clamp. Brain Res 617:87–95

    Article  PubMed  CAS  Google Scholar 

  38. Liu Z, Bunney EB, Appel SB, Brodie MS (2003) Serotonin reduces the hyperpolarization-activated current (Ih) in ventral tegmental area dopamine neurons: involvement of 5-HT2 receptors and protein kinase C. J Neurophysiol 90:3201–3212

    Article  PubMed  CAS  Google Scholar 

  39. Loeb DM, Stephens RM, Copeland T, Kaplan DR, Greene LA (1994) A Trk nerve growth factor (NGF) receptor point mutation affecting interaction with phospholipase C-gamma 1 abolishes NGF-promoted peripherin induction but not neurite outgrowth. J Biol Chem 269:8901–8910

    PubMed  CAS  Google Scholar 

  40. Luo B, Prescott SM, Topham MK (2004) Diacylglycerol kinase zeta regulates phosphatidylinositol 4-phosphate 5-kinase Ialpha by a novel mechanism. Cell Signal 16:891–897

    Article  PubMed  CAS  Google Scholar 

  41. Luthi A, McCormick DA (1999) Modulation of a pacemaker current through Ca(2+)-induced stimulation of cAMP production. Nat Neurosci 2:634–641

    Article  PubMed  CAS  Google Scholar 

  42. Maeno-Hikichi Y, Chang S, Matsumura K, Lai M, Lin H, Nakagawa N, Kuroda S, Zhang JF (2003) A PKC epsilon-ENH-channel complex specifically modulates N-type Ca2+ channels. Nat Neurosci 6:468–475

    PubMed  CAS  Google Scholar 

  43. McCormick DA, Williamson A (1991) Modulation of neuronal firing mode in cat and guinea pig LGNd by histamine: possible cellular mechanisms of histaminergic control of arousal. J Neurosci 11:3188–3199

    PubMed  CAS  Google Scholar 

  44. Meakin SO, MacDonald JI, Gryz EA, Kubu CJ, Verdi JM (1999) The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation. J Biol Chem 274:9861–9870

    Article  PubMed  CAS  Google Scholar 

  45. Meyers R, Cantley LC (1997) Cloning and characterization of a wortmannin-sensitive human phosphatidylinositol 4-kinase. J Biol Chem 272:4384–4390

    Article  PubMed  CAS  Google Scholar 

  46. Mignery GA, Newton CL, Archer BT 3rd, Sudhof TC (1990) Structure and expression of the rat inositol 1,4,5-trisphosphate receptor. J Biol Chem 265:12679–12685

    PubMed  CAS  Google Scholar 

  47. Mikoshiba K, Hattori M (2000) IP3 receptor-operated calcium entry. Sci Signal Transduct Knowl Environ 2000:PE1

    Google Scholar 

  48. Nakanishi S, Catt KJ, Balla T (1995) A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids. Proc Natl Acad Sci USA 92:5317–5321

    Article  PubMed  CAS  Google Scholar 

  49. Nasuhoglu C, Feng S, Mao Y, Shammat I, Yamamato M, Earnest S, Lemmon M, Hilgemann DW (2002) Modulation of cardiac PIP2 by cardioactive hormones and other physiologically relevant interventions. Am J Physiol Cell Physiol 283:C223–C234

    PubMed  CAS  Google Scholar 

  50. Patel S, Joseph SK, Thomas AP (1999) Molecular properties of inositol 1,4,5-trisphosphate receptors. Cell Calcium 25:247–264

    Article  PubMed  CAS  Google Scholar 

  51. Pian P, Bucchi A, Robinson RB, Siegelbaum SA (2006) Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2. J Gen Physiol 128:593–604

    Article  PubMed  CAS  Google Scholar 

  52. Poolos NP, Bullis JB, Roth MK (2006) Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase. J Neurosci 26:7995–8003

    Article  PubMed  CAS  Google Scholar 

  53. Qiu DL, Chu CP, Shirasaka T, Nabekura T, Kunitake T, Kato K, Nakazato M, Katoh T, Kannan H (2003) Neuromedin U depolarizes rat hypothalamic paraventricular nucleus neurons in vitro by enhancing IH channel activity. J Neurophysiol 90:843–850

    Article  PubMed  CAS  Google Scholar 

  54. Qiu DL, Chu CP, Tsukino H, Shirasaka T, Nakao H, Kato K, Kunitake T, Katoh T, Kannan H (2005) Neuromedin U receptor-2 mRNA and HCN channels mRNA expression in NMU-sensitive neurons in rat hypothalamic paraventricular nucleus. Neurosci Lett 374:69–72

    Article  PubMed  CAS  Google Scholar 

  55. Quist E, Sanchez M (1983) Alpha adrenergic drugs induce a phospholipid effect in canine heart. Proc West Pharmacol Soc 26:333–335

    PubMed  CAS  Google Scholar 

  56. Quist E, Satumtira N, Powell P (1989) Regulation of polyphosphoinositide synthesis in cardiac membranes. Arch Biochem Biophys 271:21–32

    Article  PubMed  CAS  Google Scholar 

  57. Quist EE (1982) Evidence for a carbachol stimulated phosphatidylinositol effect in heart. Biochem Pharmacol 31:3130–3133

    Article  PubMed  CAS  Google Scholar 

  58. Quist EE, Satumtira N (1987) Muscarinic receptor stimulated phosphoinositide turnover in cardiac atrial tissue. Biochem Pharmacol 36:499–505

    Article  PubMed  CAS  Google Scholar 

  59. Ranganathan R, Malicki DM, Zuker CS (1995) Signal transduction in Drosophila photoreceptors. Annu Rev Neurosci 18:283–317

    Article  PubMed  CAS  Google Scholar 

  60. Redman C, Lefevre J, MacDonald ML (1995) Inhibition of diacylglycerol kinase by the antitumor agent calphostin C. Evidence for similarity between the active site of diacylglycerol kinase and the regulatory site of protein kinase C. Biochem Pharmacol 50:235–241

    Article  PubMed  CAS  Google Scholar 

  61. Robinson RB, Siegelbaum SA (2003) Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 65:453–480

    Article  PubMed  CAS  Google Scholar 

  62. Sekar MC, Roufogalis BD (1984) Comparison of muscarinic and alpha-adrenergic receptors in rat atria based on phosphoinositide turnover. Life Sci 35:1527–1533

    Article  PubMed  CAS  Google Scholar 

  63. Snow P, Yim DL, Leibow JD, Saini S, Nuccitelli R (1996) Fertilization stimulates an increase in inositol trisphosphate and inositol lipid levels in Xenopus eggs. Dev Biol 180:108–118

    Article  PubMed  CAS  Google Scholar 

  64. Song DK, Ashcroft FM (2001) ATP modulation of ATP-sensitive potassium channel ATP sensitivity varies with the type of SUR subunit. J Biol Chem 276:7143–7149

    Article  PubMed  CAS  Google Scholar 

  65. Suh BC, Hille B (2002) Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron 35:507–520

    Article  PubMed  CAS  Google Scholar 

  66. Suh BC, Hille B (2005) Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate. Curr Opin Neurobiol 15:370–378

    Article  PubMed  CAS  Google Scholar 

  67. Suh BC, Inoue T, Meyer T, Hille B (2006) Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science 314(5804):1454–1457

    Article  PubMed  CAS  Google Scholar 

  68. Sul D, Baron CB, Broome R, Coburn RF (2001) Smooth muscle length-dependent PI(4,5)P2 synthesis and paxillin tyrosine phosphorylation. Am J Physiol Cell Physiol 281:C300–C310

    PubMed  CAS  Google Scholar 

  69. Thoby-Brisson M, Cauli B, Champagnat J, Fortin G, Katz DM (2003) Expression of functional tyrosine kinase B receptors by rhythmically active respiratory neurons in the pre-Botzinger complex of neonatal mice. J Neurosci 23:7685–7689

    PubMed  CAS  Google Scholar 

  70. Thompson AK, Mostafapour SP, Denlinger LC, Bleasdale JE, Fisher SK (1991) The aminosteroid U-73122 inhibits muscarinic receptor sequestration and phosphoinositide hydrolysis in SK-N-SH neuroblastoma cells. A role for Gp in receptor compartmentation. J Biol Chem 266:23856–23862

    PubMed  CAS  Google Scholar 

  71. Topham MK (2006) Signaling roles of diacylglycerol kinases. J Cell Biochem 97:474–484

    Article  PubMed  CAS  Google Scholar 

  72. Trudeau MC, Zagotta WN (2002) Mechanism of calcium/calmodulin inhibition of rod cyclic nucleotide-gated channels. Proc Natl Acad Sci USA 99:8424–8429

    Article  PubMed  CAS  Google Scholar 

  73. Vargas G, Lucero MT (2002) Modulation by PKA of the hyperpolarization-activated current (Ih) in cultured rat olfactory receptor neurons. J Membr Biol 188:115–125

    Article  PubMed  CAS  Google Scholar 

  74. Vazquez G, Wedel BJ, Aziz O, Trebak M, Putney JW Jr (2004) The mammalian TRPC cation channels. Biochim Biophys Acta 1742:21–36

    Article  PubMed  CAS  Google Scholar 

  75. Violin JD, Newton AC (2003) Pathway illuminated: visualizing protein kinase C signaling. IUBMB Life 55:653–660

    Article  PubMed  CAS  Google Scholar 

  76. Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269:5241–5248

    PubMed  CAS  Google Scholar 

  77. Weisz OA, Gibson GA, Leung SM, Roder J, Jeromin A (2000) Overexpression of frequenin, a modulator of phosphatidylinositol 4-kinase, inhibits biosynthetic delivery of an apical protein in polarized madin-darby canine kidney cells. J Biol Chem 275:24341–24347

    Article  PubMed  CAS  Google Scholar 

  78. Wiesmann C, de Vos AM (2001) Nerve growth factor: structure and function. Cell Mol Life Sci 58:748–759

    Article  PubMed  CAS  Google Scholar 

  79. Winks JS, Hughes S, Filippov AK, Tatulian L, Abogadie FC, Brown DA, Marsh SJ (2005) Relationship between membrane phosphatidylinositol-4,5-bisphosphate and receptor-mediated inhibition of native neuronal M channels. J Neurosci 25:3400–3413

    Article  PubMed  CAS  Google Scholar 

  80. Womack KB, Gordon SE, He F, Wensel TG, Lu CC, Hilgemann DW (2000) Do phosphatidylinositides modulate vertebrate phototransduction? J Neurosci 20:2792–2799

    PubMed  CAS  Google Scholar 

  81. Wu JY, Cohen IS (1997) Tyrosine kinase inhibition reduces i(f) in rabbit sinoatrial node myocytes. Pflugers Arch 434:509–514

    Article  PubMed  CAS  Google Scholar 

  82. Wu L, Bauer CS, Zhen XG, Xie C, Yang J (2002) Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2. Nature 419:947–952

    Article  PubMed  CAS  Google Scholar 

  83. Xu C, Watras J, Loew LM (2003) Kinetic analysis of receptor-activated phosphoinositide turnover. J Cell Biol 161:779–791

    Article  PubMed  CAS  Google Scholar 

  84. Yu H, Chang F, Cohen IS (1995) Pacemaker current i(f) in adult canine cardiac ventricular myocytes. J Physiol 485(Pt 2):469–483

    PubMed  CAS  Google Scholar 

  85. Yu HG, Lu Z, Pan Z, Cohen IS (2004) Tyrosine kinase inhibition differentially regulates heterologously expressed HCN channels. Pflugers Arch 447:392–400

    Article  PubMed  CAS  Google Scholar 

  86. Zhainazarov AB, Spehr M, Wetzel CH, Hatt H, Ache BW (2004) Modulation of the olfactory CNG channel by Ptdlns(3,4,5)P3. J Membr Biol 201:51–57

    Article  PubMed  CAS  Google Scholar 

  87. Zhang H, Craciun LC, Mirshahi T, Rohacs T, Lopes CM, Jin T, Logothetis DE (2003) PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron 37:963–975

    Article  PubMed  CAS  Google Scholar 

  88. Zhang H, He C, Yan X, Mirshahi T, Logothetis DE (1999) Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions. Nat Cell Biol 1:183–188

    Article  PubMed  CAS  Google Scholar 

  89. Zhao X, Varnai P, Tuymetova G, Balla A, Toth ZE, Oker-Blom C, Roder J, Jeromin A, Balla T (2001) Interaction of neuronal calcium sensor-1 (NCS-1) with phosphatidylinositol 4-kinase beta stimulates lipid kinase activity and affects membrane trafficking in COS-7 cells. J Biol Chem 276:40183–40189

    PubMed  CAS  Google Scholar 

  90. Zheng Q, Bobich JA, Vidugiriene J, McFadden SC, Thomas F, Roder J, Jeromin A (2005) Neuronal calcium sensor-1 facilitates neuronal exocytosis through phosphatidylinositol 4-kinase. J Neurochem 92:442–451

    Article  PubMed  CAS  Google Scholar 

  91. Zhu JJ, Uhlrich DJ (1998) Cellular mechanisms underlying two muscarinic receptor-mediated depolarizing responses in relay cells of the rat lateral geniculate nucleus. Neuroscience 87:767–781

    Article  PubMed  CAS  Google Scholar 

  92. Zolles G, Klocker N, Wenzel D, Weisser-Thomas J, Fleischmann BK, Roeper J, Fakler B (2006) Pacemaking by HCN channels requires interaction with phosphoinositides. Neuron 52:1027–1036

    Article  PubMed  CAS  Google Scholar 

  93. Zong X, Eckert C, Yuan H, Wahl-Schott C, Abicht H, Fang L, Li R, Mistrik P, Gerstner A, Much B, Baumann L, Michalakis S, Zeng R, Chen Z, Biel M (2005) A novel mechanism of modulation of hyperpolarization-activated cyclic nucleotide-gated channels by Src kinase. J Biol Chem 280:34224–34232

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank John Riley for help with the Xenopus oocyte injections. This work was partially supported by grants NS-36658 (S.A. Siegelbaum) and HL-28958 (R.B. Robinson) from the National Institutes of Health, and the Howard Hughes Medical Institute (S.A. Siegelbaum).

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Pian, P., Bucchi, A., DeCostanzo, A. et al. Modulation of cyclic nucleotide-regulated HCN channels by PIP2 and receptors coupled to phospholipase C. Pflugers Arch - Eur J Physiol 455, 125–145 (2007). https://doi.org/10.1007/s00424-007-0295-2

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