TY - JOUR
T1 - Spatially compartmentalized phase regulation of a ca2+-camp-pka oscillatory circuit
AU - Tenner, Brian
AU - Getz, Michael
AU - Ross, Brian
AU - Ohadi, Donya
AU - Bohrer, Christopher H.
AU - Greenwald, Eric
AU - Mehta, Sohum
AU - Xiao, Jie
AU - Rangamani, Padmini
AU - Zhang, Jin
N1 - Publisher Copyright:
© Tenner et al.
PY - 2020/10
Y1 - 2020/10
N2 - Signaling networks are spatiotemporally organized to sense diverse inputs, process information, and carry out specific cellular tasks. In b 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 b 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.
AB - Signaling networks are spatiotemporally organized to sense diverse inputs, process information, and carry out specific cellular tasks. In b 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 b 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.
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U2 - 10.7554/eLife.55013
DO - 10.7554/eLife.55013
M3 - Article
C2 - 33201801
AN - SCOPUS:85096348417
SN - 2050-084X
VL - 9
SP - 1
EP - 34
JO - eLife
JF - eLife
M1 - e55013
ER -