Spatially compartmentalized phase regulation of a Ca2+-cAMP-PKA oscillatory circuit
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 17, 2020
- Source ID
- 10.7554/elife.55013
Entities
People
- Brian L Ross
- Brian Tenner
- Christopher H Bohrer
- Donya Ohadi
- Eric C Greenwald
- Jie Xiao
- Jin Zhang
- Michael Getz
- Padmini Rangamani
- Sohum Mehta
Organizations
- Johns Hopkins University
- National Institutes of Health
- National Science Foundation
- Office of Naval Research
- United States Department of Defense
- University of California, San Diego