The L-type voltage-gated Ca2+ channel is the Ca2+ sensor protein of stimulus-secretion coupling in pancreatic beta cells

Michael Trus, Richard F. Corkey, Rafael Nesher, Ann Marie T. Richard, Jude T. Deeney, Barbara E. Corkey, Daphne Atlas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

L-type voltage-gated Ca2+ channels (Cav1.2) mediate a major part of insulin secretion from pancreatic β-cells. Cav1.2, like other voltage-gated Ca2+ channels, is functionally and physically coupled to synaptic proteins. The tight temporal coupling between channel activation and secretion leads to the prediction that rearrangements within the channel can be directly transmitted to the synaptic proteins, subsequently triggering release. La3+, which binds to the polyglutamate motif (EEEE) comprising the selectivity filter, is excluded from entry into the cells and has been previously shown to support depolarization-evoked catecholamine release from chromaffin and PC12 cells. Hence, voltage-dependent trigger of release relies on Ca2+ ions bound at the EEEE motif and not on cytosolic Ca 2+ elevation. We show that glucose-induced insulin release in rat pancreatic islets and ATP release in INS-1E cells are supported by La 3+ in nominally Ca2+-free solution. The release is inhibited by nifedipine. Fura 2 imaging of dispersed islet cells exposed to high glucose and La3+ in Ca2+-free solution detected no change in fluorescence; thus, La3+ is excluded from entry, and Ca 2+ is not significantly released from intracellular stores. La 3+ by interacting extracellularlly with the EEEE motif is sufficient to support glucose-induced insulin secretion. Voltage-driven conformational changes that engage the ion/EEEE interface are relayed to the exocytotic machinery prior to ion influx, allowing for a fast and tightly regulated process of release. These results confirm that the Ca2+ channel is a constituent of the exocytotic complex [Wiser et al. (1999) PNAS 96, 248-253] and the putative Ca2+-sensor protein of release.

Original languageEnglish
Pages (from-to)14461-14467
Number of pages7
JournalBiochemistry
Volume46
Issue number50
DOIs
StatePublished - 18 Dec 2007

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