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

Author:

Tenner Brian12,Getz Michael3ORCID,Ross Brian2ORCID,Ohadi Donya4,Bohrer Christopher H1,Greenwald Eric2,Mehta Sohum2ORCID,Xiao Jie1ORCID,Rangamani Padmini34ORCID,Zhang Jin25ORCID

Affiliation:

1. Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, United States

2. Department of Pharmacology, University of California, San Diego, La Jolla, United States

3. Chemical Engineering Graduate Program, University of California, San Diego, La Jolla, United States

4. Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, United States

5. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States

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.

Funder

National Institutes of Health

U.S. Department of Defense

Office of Naval Research

National Science Foundation

Johns Hopkins University

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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