Noradrenaline inhibits exocytosis via the G protein βγ subunit and refilling of the readily releasable granule pool via the α(i1/2) subunit

J Physiol. 2010 Sep 15;588(Pt 18):3485-98. doi: 10.1113/jphysiol.2010.190090. Epub 2010 Jul 19.


The molecular mechanisms responsible for the 'distal' effect by which noradrenaline (NA) blocks exocytosis in the β-cell were examined by whole-cell and cell-attached patch clamp capacitance measurements in INS 832/13 β-cells. NA inhibited Ca(2+)-evoked exocytosis by reducing the number of exocytotic events, without modifying vesicle size. Fusion pore properties also were unaffected. NA-induced inhibition of exocytosis was abolished by a high level of Ca(2+) influx, by intracellular application of antibodies against the G protein subunit Gβ and was mimicked by the myristoylated βγ-binding/activating peptide mSIRK. NA-induced inhibition was also abolished by treatment with BoNT/A, which cleaves the C-terminal nine amino acids of SNAP-25, and also by a SNAP-25 C-terminal-blocking peptide containing the BoNT/A cleavage site. These data indicate that inhibition of exocytosis by NA is downstream of increased [Ca(2+)](i) and is mediated by an interaction between Gβγ and the C-terminus of SNAP-25, as is the case for inhibition of neurotransmitter release. Remarkably, in the course of this work, a novel effect of NA was discovered. NA induced a marked retardation of the rate of refilling of the readily releasable pool (RRP) of secretory granules. This retardation was specifically abolished by a Gα(i1/2) blocking peptide demonstrating that the effect is mediated via activation of Gα(i1) and/or Gα(i2).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / pharmacology
  • Cell Line
  • Exocytosis / physiology*
  • GTP-Binding Protein alpha Subunits / genetics
  • GTP-Binding Protein alpha Subunits / metabolism*
  • GTP-Binding Protein beta Subunits / metabolism*
  • Gene Expression Regulation
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / physiology
  • Norepinephrine / physiology*
  • Synaptosomal-Associated Protein 25 / genetics
  • Synaptosomal-Associated Protein 25 / metabolism


  • GTP-Binding Protein alpha Subunits
  • GTP-Binding Protein beta Subunits
  • Insulin
  • Synaptosomal-Associated Protein 25
  • Calcium
  • Norepinephrine