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PMID: 14569017 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Beta-adrenergic regulation requires direct anchoring of PKA to cardiac CaV1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 22 ·2003-10-28 ·Pages 13093-8

Hulme JT, Lin TW, Westenbroek RE, Scheuer T, Catterall WA

Abstract

Activation of beta-adrenergic receptors and consequent phosphorylation by cAMP-dependent protein kinase A (PKA) greatly increases the L-type Ca2+ current through CaV1.2 channels in isolated cardiac myocytes. A kinase-anchoring protein 15 (AKAP15) coimmunoprecipitates with CaV1.2 channels isolated from rat heart membrane extracts and transfected cells, and it colocalizes with CaV1.2 channels and PKA in the transverse tubules of isolated ventricular myocytes. Site-directed mutagenesis studies reveal that AKAP15 directly interacts with the distal C terminus of the cardiac CaV1.2 channel via a leucine zipper-like motif. Disruption of PKA anchoring to CaV1.2 channels via AKAP15 using competing peptides markedly inhibits the beta-adrenergic regulation of CaV1.2 channels via the PKA pathway in ventricular myocytes. These results identify a conserved leucine zipper motif in the C terminus of the CaV1 family of Ca2+ channels that directly anchors an AKAP15-PKA signaling complex to ensure rapid and efficient regulation of L-type Ca2+ currents in response to beta-adrenergic stimulation and local increases in cAMP.

MeSH Terms
A Kinase Anchor Proteins Adaptor Proteins, Signal Transducing Amino Acid Sequence Animals Binding Sites Calcium Channels, L-Type/chemistry,metabolism Carrier Proteins/chemistry,metabolism Cyclic AMP-Dependent Protein Kinases/chemistry,metabolism Heart/physiology Leucine Zippers/physiology Male Membrane Proteins/chemistry,metabolism Molecular Sequence Data Muscle, Skeletal/physiology Rabbits Rats Rats, Wistar Receptors, Adrenergic, beta/physiology Sequence Alignment Sequence Homology, Amino Acid
Chemicals
A Kinase Anchor Proteins AKAP7 protein, human Adaptor Proteins, Signal Transducing Calcium Channels, L-Type Carrier Proteins L-type calcium channel alpha(1C) Membrane Proteins Receptors, Adrenergic, beta Cyclic AMP-Dependent Protein Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Hulme Joanne T
Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA.
Lin Teddy W-C
Westenbroek Ruth E
Scheuer Todd
Catterall William A
References (56)
56 references, click to expand
  1. Alternative splicing regulates the subcellular localization of A-kinase anchoring protein 18 isoforms.
    J Cell Biol. 1999 Dec 27;147(7):1481-92 PMID: 10613906
  2. Regulation of ion channels by cAMP-dependent protein kinase and A-kinase anchoring proteins.
    Curr Opin Neurobiol. 1998 Jun;8(3):330-4 PMID: 9687361
  3. Proteolytic processing of the C terminus of the alpha(1C) subunit of L-type calcium channels and the role of a proline-rich domain in membrane tethering of proteolytic fragments.
    J Biol Chem. 2000 Mar 24;275(12):8556-63 PMID: 10722694
  4. Nomenclature of voltage-gated calcium channels.
    Neuron. 2000 Mar;25(3):533-5 PMID: 10774722
  5. Dopaminergic modulation of voltage-gated Na+ current in rat hippocampal neurons requires anchoring of cAMP-dependent protein kinase.
    J Neurosci. 1999 Sep 1;19(17):RC21 PMID: 10460275
  6. Structure and regulation of voltage-gated Ca2+ channels.
    Annu Rev Cell Dev Biol. 2000;16:521-55 PMID: 11031246
  7. mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module.
    EMBO J. 2001 Apr 17;20(8):1921-30 PMID: 11296225
  8. Phosphorylation-dependent regulation of ryanodine receptors: a novel role for leucine/isoleucine zippers.
    J Cell Biol. 2001 May 14;153(4):699-708 PMID: 11352932
  9. C-terminal fragments of the alpha 1C (CaV1.2) subunit associate with and regulate L-type calcium channels containing C-terminal-truncated alpha 1C subunits.
    J Biol Chem. 2001 Jun 15;276(24):21089-97 PMID: 11274161
  10. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel.
    Science. 2002 Jan 18;295(5554):496-9 PMID: 11799244
  11. Cardiac excitation-contraction coupling.
    Nature. 2002 Jan 10;415(6868):198-205 PMID: 11805843
  12. A novel leucine zipper targets AKAP15 and cyclic AMP-dependent protein kinase to the C terminus of the skeletal muscle Ca2+ channel and modulates its function.
    J Biol Chem. 2002 Feb 8;277(6):4079-87 PMID: 11733497
  13. Novel functional properties of Ca(2+) channel beta subunits revealed by their expression in adult rat heart cells.
    J Physiol. 2002 Jun 1;541(Pt 2):435-52 PMID: 12042350
  14. Trafficking of L-type calcium channels mediated by the postsynaptic scaffolding protein AKAP79.
    J Biol Chem. 2002 Sep 13;277(37):33598-603 PMID: 12114507
  15. The dependence of slow inward current in Purkinje fibres on the extracellular calcium-concentration.
    J Physiol. 1967 Sep;192(2):479-92 PMID: 6050160
  16. Adrenaline-like effects of intracellular iontophoresis of cyclic AMP in cardiac Purkinje fibres.
    Nat New Biol. 1973 Sep 26;245(143):120-2 PMID: 4355672
  17. Localization of beta adrenergic receptors, and effects of noradrenaline and cyclic nucleotides on action potentials, ionic currents and tension in mammalian cardiac muscle.
    J Physiol. 1974 Oct;242(2):429-51 PMID: 4376168
  18. Properties of two inward membrane currents in the heart.
    Annu Rev Physiol. 1979;41:413-24 PMID: 373598
  19. Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current.
    Nature. 1982 Aug 5;298(5874):576-8 PMID: 6285199
  20. Calcium channel modulation by neurotransmitters, enzymes and drugs.
    Nature. 1983 Feb 17-23;301(5901):569-74 PMID: 6131381
  21. Phosphorylation of the calcium antagonist receptor of the voltage-sensitive calcium channel by cAMP-dependent protein kinase.
    Proc Natl Acad Sci U S A. 1985 Apr;82(8):2528-32 PMID: 2581248
  22. Mechanisms of calcium channel modulation by beta-adrenergic agents and dihydropyridine calcium agonists.
    J Mol Cell Cardiol. 1986 Jul;18(7):691-710 PMID: 2427730
  23. Purified dihydropyridine-binding site from skeletal muscle t-tubules is a functional calcium channel.
    Nature. 1986 Sep 4-10;323(6083):66-8 PMID: 2427959
  24. The bovine cardiac receptor for calcium channel blockers is a 195-kDa protein.
    Eur J Biochem. 1988 Jun 1;174(2):369-75 PMID: 2838274
  25. Sequence and expression of mRNAs encoding the alpha 1 and alpha 2 subunits of a DHP-sensitive calcium channel.
    Science. 1988 Sep 23;241(4873):1661-4 PMID: 2458626
  26. Primary structure and functional expression of the cardiac dihydropyridine-sensitive calcium channel.
    Nature. 1989 Jul 20;340(6230):230-3 PMID: 2474130
  27. Primary structure of the beta subunit of the DHP-sensitive calcium channel from skeletal muscle.
    Science. 1989 Sep 8;245(4922):1115-8 PMID: 2549640
  28. Subunits of purified calcium channels: a 212-kDa form of alpha 1 and partial amino acid sequence of a phosphorylation site of an independent beta subunit.
    Proc Natl Acad Sci U S A. 1989 Nov;86(21):8585-9 PMID: 2554320
  29. Characterization of the two size forms of the alpha 1 subunit of skeletal muscle L-type calcium channels.
    Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10778-82 PMID: 1720551
  30. The A-kinase anchor protein MAP2B and cAMP-dependent protein kinase are associated with class C L-type calcium channels in neurons.
    J Biol Chem. 1999 Oct 15;274(42):30280-7 PMID: 10514522
  31. 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
  32. Association of the type II cAMP-dependent protein kinase with a human thyroid RII-anchoring protein. Cloning and characterization of the RII-binding domain.
    J Biol Chem. 1992 Jul 5;267(19):13376-82 PMID: 1618839
  33. Cyclic AMP-dependent phosphorylation and regulation of the cardiac dihydropyridine-sensitive Ca channel.
    FEBS Lett. 1992 Sep 14;309(3):343-9 PMID: 1325377
  34. Biochemical properties and subcellular distribution of an N-type calcium channel alpha 1 subunit.
    Neuron. 1992 Dec;9(6):1099-115 PMID: 1334419
  35. Differential phosphorylation of two size forms of the neuronal class C L-type calcium channel alpha 1 subunit.
    J Biol Chem. 1993 Sep 15;268(26):19451-7 PMID: 8396138
  36. Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel alpha 1 subunits.
    J Cell Biol. 1993 Nov;123(4):949-62 PMID: 8227151
  37. Voltage-dependent potentiation of the activity of cardiac L-type calcium channel alpha 1 subunits due to phosphorylation by cAMP-dependent protein kinase.
    Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10135-9 PMID: 7694283
  38. Regulation of the cloned L-type cardiac calcium channel by cyclic-AMP-dependent protein kinase.
    FEBS Lett. 1994 Apr 4;342(2):119-23 PMID: 8143862
  39. Localization of A-kinase through anchoring proteins.
    Mol Endocrinol. 1994 Jan;8(1):5-11 PMID: 8152430
  40. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells.
    Physiol Rev. 1994 Apr;74(2):365-507 PMID: 8171118
  41. Voltage-dependent potentiation of L-type Ca2+ channels in skeletal muscle cells requires anchored cAMP-dependent protein kinase.
    Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11492-6 PMID: 7972090
  42. A kinase anchor proteins and the intracellular targeting of signals carried by cyclic AMP.
    Biochim Biophys Acta. 1994 Dec 30;1224(3):467-79 PMID: 7803506
  43. Cardiac calcium channels expressed in Xenopus oocytes are modulated by dephosphorylation but not by cAMP-dependent phosphorylation.
    Receptors Channels. 1994;2(3):215-26 PMID: 7874448
  44. On the regulation of the expressed L-type calcium channel by cAMP-dependent phosphorylation.
    Pflugers Arch. 1995 Jul;430(3):340-7 PMID: 7491257
  45. Specific phosphorylation of a site in the full-length form of the alpha 1 subunit of the cardiac L-type calcium channel by adenosine 3',5'-cyclic monophosphate-dependent protein kinase.
    Biochemistry. 1996 Aug 13;35(32):10392-402 PMID: 8756695
  46. In-vivo phosphorylation of the cardiac L-type calcium channel beta-subunit in response to catecholamines.
    Mol Cell Biochem. 1996 Oct-Nov;163-164:99-106 PMID: 8974044
  47. Modulation of the cloned skeletal muscle L-type Ca2+ channel by anchored cAMP-dependent protein kinase.
    J Neurosci. 1997 Feb 15;17(4):1243-55 PMID: 9006969
  48. Identification of a 15-kDa cAMP-dependent protein kinase-anchoring protein associated with skeletal muscle L-type calcium channels.
    J Biol Chem. 1997 Mar 7;272(10):6297-302 PMID: 9045648
  49. Protein kinase A anchoring.
    J Biol Chem. 1997 May 16;272(20):12881-4 PMID: 9190362
  50. Identification and subcellular localization of the subunits of L-type calcium channels and adenylyl cyclase in cardiac myocytes.
    J Biol Chem. 1997 Aug 1;272(31):19401-7 PMID: 9235939
  51. Differential effects of subunit interactions on protein kinase A- and C-mediated phosphorylation of L-type calcium channels.
    Biochemistry. 1997 Aug 5;36(31):9605-15 PMID: 9236007
  52. cAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits.
    Neuron. 1997 Jul;19(1):185-96 PMID: 9247274
  53. A novel lipid-anchored A-kinase Anchoring Protein facilitates cAMP-responsive membrane events.
    EMBO J. 1998 Apr 15;17(8):2261-72 PMID: 9545239
  54. Primary structure and function of an A kinase anchoring protein associated with calcium channels.
    Neuron. 1998 May;20(5):1017-26 PMID: 9620705
  55. A-kinase anchoring protein 100 (AKAP100) is localized in multiple subcellular compartments in the adult rat heart.
    J Cell Biol. 1998 Jul 27;142(2):511-22 PMID: 9679148
  56. Effect of acidosis on transient outward potassium current in isolated rat ventricular myocytes.
    Am J Physiol Heart Circ Physiol. 2000 Jan;278(1):H50-9 PMID: 10644583
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.2135335100
Published
2003-10-28
Epub
2003-00-20
Pages
13093-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC240750
Subset
IM
Grants
NHLBI NIH HHS · P01 HL044948 · United States
NHLBI NIH HHS · P01 HL 44948 · United States
External Links
PubMed source DOI: 10.1073/pnas.2135335100 PMC Full Text View journal details
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