Spatially compartmentalized phase regulation of a Ca2+-cAMP-PKA oscillatory circuit

Elife. 2020 Nov 17;9:e55013. doi: 10.7554/eLife.55013.


Signaling networks are spatiotemporally organized to sense diverse inputs, process information, and carry out specific cellular tasks. In β cells, Ca2+, cyclic adenosine monophosphate (cAMP), and Protein Kinase A (PKA) exist in an oscillatory circuit characterized by a high degree of feedback. Here, we describe a mode of regulation within this circuit involving a spatial dependence of the relative phase between cAMP, PKA, and Ca2+. We show that in mouse MIN6 β cells, nanodomain clustering of Ca2+-sensitive adenylyl cyclases (ACs) drives oscillations of local cAMP levels to be precisely in-phase with Ca2+ oscillations, whereas Ca2+-sensitive phosphodiesterases maintain out-of-phase oscillations outside of the nanodomain. Disruption of this precise phase relationship perturbs Ca2+ oscillations, suggesting the relative phase within an oscillatory circuit can encode specific functional information. This work unveils a novel mechanism of cAMP compartmentation utilized for localized tuning of an oscillatory circuit and has broad implications for the spatiotemporal regulation of signaling networks.

Keywords: biochemistry; cAMP; chemical biology; computational biology; mouse; pancreatic beta cell; signaling compartmentalization; systems biology.

Publication types

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

MeSH terms

  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism
  • Animals
  • Calcium / metabolism*
  • Calcium Signaling / physiology
  • Cell Line
  • Cell Membrane
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Mice
  • Models, Biological
  • Signal Transduction
  • Single-Cell Analysis


  • A Kinase Anchor Proteins
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium