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Cited by 284Cellular transport and secretionIon channel regulation and functionCalcium signaling and nucleotide metabolism

The voltage sensitive Lc-type Ca 2+ channel is functionally coupled to the exocytotic machinery

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Wiser, Ofer, Trus, Michael, Hernández, Ana, Renström, Erik, Barg, Sebastian, Rorsman, Patrik, Atlas, Daphne·1999·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.96.1.248PMC PMC15125
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Abstract

Although N- and P-type Ca 2+ channels predominant in fast-secreting systems, Lc-type Ca 2+ channels (C-class) can play a similar role in certain secretory cells and synapses. For example, in retinal bipolar cells, Ca 2+ entry through the Lc channels triggers ultrafast exocytosis, and in pancreatic β-cells, evoked secretion is highly sensitive to Ca 2+ . These findings suggest that a rapidly release pool of vesicles colocalizes with the Ca 2+ channels to allow high Ca 2+ concentration and a tight coupling of the Lc channels at the release site. In binding studies, we show that the Lc channel is physically associated with synaptotagmin (p65) and the soluble N-ethylmaleimide-sensitive attachment proteins receptors: syntaxin and synaptosomal-associated protein of 25 kDa. Soluble N-ethylmaleimide-sensitive attachent proteins receptors coexpressed in Xenopus oocytes along with the Lc channel modify the kinetic properties of the channel. The modulatory action of syntaxin can be overcome by coexpressing p65, where at a certain ratio of p65/syntaxin, the channel regains its unaltered kinetic parameters. The cytosolic region of the channel, Lc 753–893 , separating repeats II–III of its α1C subunit, interacts with p65 and “pulls” down native p65 from rat brain membranes. Lc 753–893 injected into single insulin-secreting β-cell, inhibits secretion in response to channel opening, but not in response to photolysis of caged Ca 2+ , nor does it affect Ca 2+ current. These results suggest that Lc 753–893 competes with the endogenous channel for the synaptic proteins and disrupts the spatial coupling with the secretory apparatus. The molecular organization of the Lc channel and the secretory machinery into a multiprotein complex (named excitosome) appears to be essential for an effective depolarization evoked exocytosis.

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  • Exocytosis evoked by a train of depolarizations or photorelease of caged Ca2+, two conditions that can be assumed to produce a high [Ca2+]i throughout the β-cell, was unaffected by the synprint peptide.

    “Exocytosis evoked by a train of depolarizations (48) or photorelease of caged Ca2+ (731), two conditions that can be assumed to produce a high [Ca2+]I throughout the β-cell, was unaffected by the synprint peptide.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [731]

    The Discussion reports that exocytosis could still be elicited by photorelease of caged Ca2+ or a train of depolarizations in the presence of Lc753–893, with a global rather than localized calcium increase. But the paper identifies the tested peptide as Lc753–893; it uses “synprint” for an N-type channel peptide discussed in connection with previous studies, so the peptide identification is not supported. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Infusion of an excess of recombinant synprint peptide into the β-cell cytosol causes selective loss of rapid exocytosis.

    “The importance of the interaction between the Ca2+ channels and secretory granules for rapid exocytosis is illustrated by the selective loss of rapid exocytosis following infusion of an excess of recombinant synprint peptide into the β-cell cytosol (731) (Figure 20B).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [731]

    The Results (page not available) show that a recombinant Lc-channel II–III loop peptide, Lc753–893, was infused into β-cells and nearly abolished depolarization-evoked exocytosis. But the paper does not show selective loss of a rapid phase: it reports inhibition of depolarization-evoked exocytosis overall, while rapid secretion elicited by photoreleased Ca²⁺ remained intact. The Discussion (page not available) uses “synprint” for an N-channel peptide discussed in previous studies, rather than explicitly naming the infused Lc peptide synprint. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The interaction between Ca2+ channels and secretory granules is mediated by residues 753-893 of the Cav1.2 Ca2+ channel, corresponding to the intracellular loop between the 2nd and 3rd homologous domain of the α1-subunit.

    “This interaction is mediated by residues 753-893 of the Cav1.2 Ca2+ channel, which correspond to the intracellular loop between the 2nd and the 3rd homologous domain of the α1-subunit (731).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [731]

  • There is evidence that Ca2+ channels are physically anchored to the secretory granules.

    “There is evidence that Ca2+ channels are physically anchored to the secretory granules (Figure 20).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [731]

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Cited by

Sorted by citations

Authors
Wiser, O., Trus, M., Hernández, A., Renström, E., Barg, S., Rorsman, P., & Atlas, D.
Affiliations
  • Lund University (SE)
  • Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904 Israel; and Physiological Sciences, University of Lund Helgonavagen 5, S-223 62 Lund, Sweden
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1999-01-05
Volume
96
Issue
1
Pages
248-253
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.96.1.248
PMC
PMC15125
OpenAlex
W2010986301
Cited by
284
References
0
Citations by year
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FWCI
6.45
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
L-type calcium channels, synaptic vesicle exocytosis, synaptotagmin, syntaxin, retinal bipolar cells
MeSH terms
Insulin Secretion, Amino Acid Sequence, Animals, Calcium-Binding Proteins, Egtazic Acid, Electric Conductivity, Exocytosis, Insulin, Islets of Langerhans, Membrane Glycoproteins, Membrane Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Photolysis, Recombinant Fusion Proteins, Synaptosomes, Calcium Channels, Calcium Signaling, Qa-SNARE Proteins, Synaptosomal-Associated Protein 25, Synaptotagmins, Synaptotagmin I, Mice, Rats

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