Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release

Yonatan M. Kupchik, Grigory Rashkovan, Lily Ohana, Tal Keren-Raifman, Nathan Dascal, Hanna Parnas, Itzchak Parnas

Research output: Contribution to journalArticlepeer-review

Abstract

Ca2+ is essential for physiological depolarization-evoked synchronous neurotransmitter release. But, whether Ca2+ influx or another factor controls release initiation is still under debate. The time course of ACh release is controlled by a presynaptic inhibitory G protein-coupled autoreceptor (GPCR), whose agonist-binding affinity is voltage-sensitive. However, the relevance of this property for release control is not known. To resolve this question, we used pertussis toxin (PTX), which uncouples GPCR from its Gi/o and in turn reduces the affinity of GPCR toward its agonist. We show that PTX enhances ACh and glutamate release (in mice and crayfish, respectively) and, most importantly, alters the time course of release without affecting Ca2+ currents. These effects are not mediated by Gβγ because its microinjection into the presynaptic terminal did not alter the time course of release. Also, PTX reduces the association of the GPCR with the exocytotic machinery, and this association is restored by the addition of agonist. We offer the following mechanism for control of initiation and termination of physiological depolarization-evoked transmitter release. At rest, release is under tonic block achieved by the transmitter-bound high-affinity presynaptic GPCR interacting with the exocytotic machinery. Upon depolarization, the GPCR uncouples from its G protein and consequently shifts to a low-affinity state toward the transmitter. The transmitter dissociates, the unbound GPCR detaches from the exocytotic machinery, and the tonic block is alleviated. The free machinery, together with Ca2+ that had already entered, initiates release. Release terminates when the reverse occurs upon repolarization.

Original languageEnglish
Pages (from-to)4435-4440
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number11
DOIs
StatePublished - 18 Mar 2008

Keywords

  • G protein-coupled receptor
  • Neurotransmitter release
  • Pertussis toxin
  • Presynaptic receptors

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