Home LiteratureArticle Details
PMID: 10436038 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Biphasic, opposing modulation of cloned neuronal alpha1E Ca channels by distinct signaling pathways coupled to M2 muscarinic acetylcholine receptors.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 19 ·No. 16 ·1999-08-15 ·Pages 6806-17

Meza U, Bannister R, Melliti K, Adams B

Abstract

Neuronal alpha1E subunits are thought to form R-type Ca channels. When expressed in human embryonic kidney cells with M2 muscarinic acetylcholine receptors, Ca channels encoded by rabbit alpha1E exhibit striking biphasic modulation. Receptor activation first produces rapid inhibition of current amplitude and activation rate. However, in the continued presence of agonist, alpha1E currents subsequently increase. Kinetic slowing persists during this secondary stimulation phase. After receptor deactivation, kinetic slowing is quickly relieved, and current amplitude over-recovers before returning toward control levels. These features indicate that inhibition and stimulation of alpha1E are separate processes, with stimulation superimposed on inhibition. Pertussis toxin eliminates inhibition without affecting stimulation, demonstrating that inhibition and stimulation involve distinct signaling pathways. Neither inhibition nor stimulation is altered by coexpression of Ca channel beta2a or beta3 subunits. Stimulation is abolished by staurosporine and reduced by intracellular 5'-adenylylimidodiphosphate, suggesting that phosphorylation is required. However, stimulation does not seem to involve cAMP-dependent protein kinase, protein kinase C, cGMP-dependent protein kinase, tyrosine kinases, or phosphoinositide 3-kinases. Stimulation does not require a Ca signal, because it is not specifically altered by varying intracellular Ca buffering or by substituting Ba as the charge carrier. In contrast to those formed by alpha1E, Ca channels formed by alpha1A or alpha1B display only inhibition and no stimulation during prolonged activation of M2 receptors. The dual modulation of alpha1E may confer unique physiological properties on native R-type Ca channels. As one possibility, R-type channels may continue to mediate Ca influx during steady inhibition of N-type and P/Q-type channels by muscarinic or other receptors.

MeSH Terms
Animals Calcium Channels/physiology Cell Line Cloning, Molecular Cyclic AMP-Dependent Protein Kinases/metabolism Cyclic GMP-Dependent Protein Kinases Humans Neurons/physiology Patch-Clamp Techniques Pertussis Toxin Phosphorylation Protein Kinase C/metabolism Protein Kinases/metabolism Rabbits Receptors, Muscarinic/physiology Signal Transduction/physiology Stimulation, Chemical Virulence Factors, Bordetella/pharmacology
Chemicals
Calcium Channels Receptors, Muscarinic Virulence Factors, Bordetella Pertussis Toxin Protein Kinases Cyclic AMP-Dependent Protein Kinases Cyclic GMP-Dependent Protein Kinases Protein Kinase C
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Meza U
Department of Physiology and Biophysics, University of Iowa, College of Medicine, Iowa City, Iowa 52242-1109, USA.
Bannister R
Melliti K
Adams B
References (80)
80 references, click to expand
  1. Elementary events underlying voltage-dependent G-protein inhibition of N-type calcium channels.
    Biophys J. 1996 Nov;71(5):2509-21 PMID: 8913590
  2. Regulators of G protein signaling attenuate the G protein-mediated inhibition of N-type Ca channels.
    J Gen Physiol. 1999 Jan;113(1):97-110 PMID: 9874691
  3. Pertussis toxin-catalyzed ADP-ribosylation of G(o) alpha with mutations at the carboxyl terminus.
    Biochemistry. 1992 Aug 25;31(33):7736-40 PMID: 1510959
  4. Antisense oligonucleotides against alpha1E reduce R-type calcium currents in cerebellar granule cells.
    Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7760-5 PMID: 9636224
  5. Transfected muscarinic acetylcholine receptors selectively couple to Gi-type G proteins and Gq/11.
    Mol Pharmacol. 1994 May;45(5):890-8 PMID: 8190105
  6. The tyrosine kinase inhibitor genistein directly inhibits GABAA receptors.
    Brain Res Mol Brain Res. 1999 Apr 6;67(1):177-83 PMID: 10101245
  7. Biochemical properties and subcellular distribution of the neuronal class E calcium channel alpha 1 subunit.
    J Neurosci. 1995 Oct;15(10):6419-32 PMID: 7472405
  8. The long isoform of the rat thyrotropin-releasing hormone receptor down-regulates Gq proteins.
    J Biol Chem. 1994 Aug 5;269(31):19933-40 PMID: 8051077
  9. Rat brain expresses an alternatively spliced form of the dihydropyridine-sensitive L-type calcium channel alpha 2 subunit.
    Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3251-5 PMID: 1314383
  10. Activation of protein tyrosine kinase PYK2 by the m1 muscarinic acetylcholine receptor.
    Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5051-6 PMID: 9560226
  11. Cloning and expression of a cardiac/brain beta subunit of the L-type calcium channel.
    J Biol Chem. 1992 Jan 25;267(3):1792-7 PMID: 1370480
  12. Transmitter modulation of neuronal calcium channels.
    J Membr Biol. 1997 Jan 1;155(1):1-10 PMID: 9002420
  13. Muscarinic receptor activation modulates Ca2+ channels in rat intracardiac neurons via a PTX- and voltage-sensitive pathway.
    J Neurophysiol. 1997 Sep;78(3):1476-90 PMID: 9310437
  14. Expression of functional acetylcholine receptor from cloned cDNAs.
    Nature. 1984 Feb 16-22;307(5952):604-8 PMID: 6320016
  15. Inversion of Ca2+ current modulation during recovery of neuroblastoma cells from pertussis toxin pretreatment.
    FEBS Lett. 1993 Nov 22;334(3):322-6 PMID: 7902295
  16. Distinctive functional properties of the neuronal BII (class E) calcium channel.
    Receptors Channels. 1994;2(4):303-14 PMID: 7719708
  17. Mechanism of auxiliary subunit modulation of neuronal alpha1E calcium channels.
    J Gen Physiol. 1998 Aug;112(2):125-43 PMID: 9689023
  18. Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons.
    J Neurosci. 1995 Apr;15(4):2995-3012 PMID: 7722641
  19. Structure and functional expression of a member of the low voltage-activated calcium channel family.
    Science. 1993 May 21;260(5111):1133-6 PMID: 8388125
  20. ADP-ribosylation of membrane proteins catalyzed by cholera toxin: basis of the activation of adenylate cyclase.
    Proc Natl Acad Sci U S A. 1978 Jul;75(7):3050-4 PMID: 210449
  21. Voltage-dependent modulation of N-type calcium channels by G-protein beta gamma subunits.
    Nature. 1996 Mar 21;380(6571):255-8 PMID: 8637575
  22. Inhibition of the interaction of G protein G(o) with calcium channels by the calcium channel beta-subunit in rat neurones.
    J Physiol. 1995 Jun 1;485 ( Pt 2):365-72 PMID: 7666364
  23. Glutamate metabotropic receptor inhibition of voltage-gated calcium currents in visceral sensory neurons.
    J Neurophysiol. 1994 Jul;72(1):421-30 PMID: 7965024
  24. Functional expression of rat brain cloned alpha1E calcium channels in COS-7 cells.
    Pflugers Arch. 1997 Feb;433(4):523-32 PMID: 9000432
  25. Protein kinase C disrupts cannabinoid actions by phosphorylation of the CB1 cannabinoid receptor.
    J Neurosci. 1998 Apr 15;18(8):2834-41 PMID: 9526000
  26. Determinants of the G protein-dependent opioid modulation of neuronal calcium channels.
    Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1486-91 PMID: 8643659
  27. Structure and functional characterization of neuronal alpha 1E calcium channel subtypes.
    J Biol Chem. 1994 Sep 2;269(35):22347-57 PMID: 8071363
  28. Unique regulatory properties of the type 2a Ca2+ channel beta subunit caused by palmitoylation.
    Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4690-5 PMID: 9539800
  29. Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice.
    Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1692-7 PMID: 9990086
  30. Modulation of ion-channel function by G-protein-coupled receptors.
    Trends Neurosci. 1994 Dec;17(12):531-6 PMID: 7532338
  31. RGS3 inhibits G protein-mediated signaling via translocation to the membrane and binding to Galpha11.
    Mol Cell Biol. 1999 Jan;19(1):714-23 PMID: 9858594
  32. Molecular cloning and characterization of a novel calcium channel from rabbit brain.
    FEBS Lett. 1992 Aug 10;308(1):7-13 PMID: 1379552
  33. R-type Ca2+ currents evoke transmitter release at a rat central synapse.
    Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4720-5 PMID: 9539805
  34. An M2 muscarinic receptor subtype coupled to both adenylyl cyclase and phosphoinositide turnover.
    Science. 1987 Oct 30;238(4827):672-5 PMID: 2823384
  35. Primary structure and functional expression from complementary DNA of a brain calcium channel.
    Nature. 1991 Apr 4;350(6317):398-402 PMID: 1849233
  36. Augmentation of calcium channel currents in response to G protein activation by GTP gamma S in chick sensory neurons.
    J Neurosci. 1994 Aug;14(8):4847-53 PMID: 8046455
  37. Expression of RGS2 alters the coupling of metabotropic glutamate receptor 1a to M-type K+ and N-type Ca2+ channels.
    Neuron. 1999 Apr;22(4):819-29 PMID: 10230801
  38. Distribution of m1-m4 muscarinic receptor proteins in the rat striatum: light and electron microscopic immunocytochemistry using subtype-specific antibodies.
    J Neurosci. 1994 May;14(5 Pt 2):3351-63 PMID: 8182478
  39. Identification of palmitoylation sites within the L-type calcium channel beta2a subunit and effects on channel function.
    J Biol Chem. 1996 Oct 25;271(43):26465-8 PMID: 8900112
  40. Direct interaction of gbetagamma with a C-terminal gbetagamma-binding domain of the Ca2+ channel alpha1 subunit is responsible for channel inhibition by G protein-coupled receptors.
    Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8866-71 PMID: 9238069
  41. Subunit identification and reconstitution of the N-type Ca2+ channel complex purified from brain.
    Science. 1993 Jul 23;261(5120):486-9 PMID: 8392754
  42. Characterization of presynaptic calcium channels with omega-conotoxin MVIIC and omega-grammotoxin SIA: role for a resistant calcium channel type in neurosecretion.
    Mol Pharmacol. 1995 Feb;47(2):348-53 PMID: 7870043
  43. Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes.
    Nature. 1988 Aug 4;334(6181):434-7 PMID: 2841607
  44. Gbetagamma dimers stimulate vascular L-type Ca2+ channels via phosphoinositide 3-kinase.
    FASEB J. 1999 Apr;13(6):685-94 PMID: 10094929
  45. Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels.
    J Biol Chem. 1999 Jan 8;274(2):693-702 PMID: 9873004
  46. Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence.
    Nature. 1989 Jul 13;340(6229):153-6 PMID: 2567963
  47. 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
  48. Metabotropic glutamate receptor modulation of voltage-gated Ca2+ channels involves multiple receptor subtypes in cortical neurons.
    J Neurosci. 1996 Jan;16(1):36-45 PMID: 8613803
  49. Crosstalk between G proteins and protein kinase C mediated by the calcium channel alpha1 subunit.
    Nature. 1997 Jan 30;385(6615):442-6 PMID: 9009192
  50. Membrane targeting of L-type calcium channels. Role of palmitoylation in the subcellular localization of the beta2a subunit.
    J Biol Chem. 1998 Sep 4;273(36):23590-7 PMID: 9722599
  51. Localization of Ca2+ channel subtypes on rat spinal motor neurons, interneurons, and nerve terminals.
    J Neurosci. 1998 Aug 15;18(16):6319-30 PMID: 9698323
  52. G-Protein-dependent facilitation of neuronal alpha1A, alpha1B, and alpha1E Ca channels.
    J Neurosci. 1998 Jul 15;18(14):5240-52 PMID: 9651207
  53. Pertussis toxin-catalyzed ADP-ribosylation of transducin. Cysteine 347 is the ADP-ribose acceptor site.
    J Biol Chem. 1985 Nov 25;260(27):14428-30 PMID: 3863818
  54. Identification of the amino terminus of neuronal Ca2+ channel alpha1 subunits alpha1B and alpha1E as an essential determinant of G-protein modulation.
    J Neurosci. 1998 Jul 1;18(13):4815-24 PMID: 9634547
  55. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
    Pflugers Arch. 1981 Aug;391(2):85-100 PMID: 6270629
  56. Determinants of PKC-dependent modulation of a family of neuronal calcium channels.
    Neuron. 1995 Oct;15(4):929-40 PMID: 7576641
  57. Ras-dependent activation of MAP kinase pathway mediated by G-protein beta gamma subunits.
    Nature. 1994 Jun 2;369(6479):418-20 PMID: 8196770
  58. Enhancement of N- and L-type calcium channel currents by protein kinase C in frog sympathetic neurons.
    Neuron. 1993 Feb;10(2):127-36 PMID: 8382496
  59. Intracellular Ca2+ buffers disrupt muscarinic suppression of Ca2+ current and M current in rat sympathetic neurons.
    Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):652-6 PMID: 1846449
  60. RGS16 attenuates galphaq-dependent p38 mitogen-activated protein kinase activation by platelet-activating factor.
    J Biol Chem. 1999 Jan 29;274(5):2851-7 PMID: 9915820
  61. Novel form of crosstalk between G protein and tyrosine kinase pathways.
    Proc Natl Acad Sci U S A. 1997 May 13;94(10):5417-21 PMID: 9144252
  62. Modulation of Ca2+ channels by G-protein beta gamma subunits.
    Nature. 1996 Mar 21;380(6571):258-62 PMID: 8637576
  63. Sensory neuron N-type calcium currents are inhibited by both voltage-dependent and -independent mechanisms.
    Pflugers Arch. 1994 Oct;428(5-6):499-507 PMID: 7838672
  64. Gi alpha 3 and G(o) alpha selectively associate with the cloned somatostatin receptor subtype SSTR2.
    J Biol Chem. 1993 May 25;268(15):10721-7 PMID: 8098703
  65. Direct binding of G-protein betagamma complex to voltage-dependent calcium channels.
    Nature. 1997 Jan 30;385(6615):446-50 PMID: 9009193
  66. G-protein modulation of neuronal class E (alpha 1E) calcium channel expressed in GH3 cells.
    Biochem Biophys Res Commun. 1996 Mar 18;220(2):453-8 PMID: 8645326
  67. Genistein elicits biphasic effects on L-type Ca2+ current in feline atrial myocytes.
    Am J Physiol. 1998 Jul;275(1):H204-12 PMID: 9688915
  68. Tyrosine kinase-dependent suppression of a potassium channel by the G protein-coupled m1 muscarinic acetylcholine receptor.
    Cell. 1993 Dec 17;75(6):1145-56 PMID: 8261514
  69. Cholera toxin induces cAMP-independent degradation of Gs.
    J Biol Chem. 1989 Apr 5;264(10):5352-7 PMID: 2538415
  70. Reconstitution of agonist-stimulated phosphatidylinositol 4,5-bisphosphate hydrolysis using purified m1 muscarinic receptor, Gq/11, and phospholipase C-beta 1.
    J Biol Chem. 1992 Apr 25;267(12):8081-8 PMID: 1341877
  71. Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors.
    EMBO J. 1987 Dec 20;6(13):3923-9 PMID: 3443095
  72. Subunit regulation of the human brain alpha 1E calcium channel.
    J Membr Biol. 1997 Nov 15;160(2):127-40 PMID: 9354705
  73. A diffusible second messenger mediates one of the pathways coupling receptors to calcium channels in rat sympathetic neurons.
    Neuron. 1991 Jun;6(6):859-67 PMID: 1647174
  74. Localization of a family of muscarinic receptor mRNAs in rat brain.
    J Neurosci. 1988 Dec;8(12):4646-52 PMID: 3199198
  75. Cholera toxin impairment of opioid-mediated inhibition of adenylate cyclase in neuroblastoma x glioma hybrid cells is due to a toxin-induced decrease in opioid receptor levels.
    Biochem J. 1991 Apr 1;275 ( Pt 1):175-81 PMID: 1673334
  76. Primary structure and functional expression of the omega-conotoxin-sensitive N-type calcium channel from rabbit brain.
    Neuron. 1993 Apr;10(4):585-98 PMID: 8386525
  77. Direct block of voltage-sensitive sodium channels by genistein, a tyrosine kinase inhibitor.
    J Pharmacol Exp Ther. 1997 Feb;280(2):521-6 PMID: 9023259
  78. G-protein beta-subunit specificity in the fast membrane-delimited inhibition of Ca2+ channels.
    J Neurosci. 1998 Nov 15;18(22):9163-70 PMID: 9801356
  79. Voltage-dependent modulation of single N-Type Ca2+ channel kinetics by receptor agonists in IMR32 cells.
    Biophys J. 1996 May;70(5):2144-54 PMID: 9172738
  80. Differential regulation of mitogen-activated protein kinase kinase 4 (MKK4) and 7 (MKK7) by signaling from G protein beta gamma subunit in human embryonal kidney 293 cells.
    J Biol Chem. 1999 Jan 22;274(4):1957-65 PMID: 9890951
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
1999-08-15
Pages
6806-17
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6782876
Subset
IM
Grants
NINDS NIH HHS · NS34423 · United States
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2