期刊
ELIFE
卷 9, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.55013
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类别
资金
- National Institutes of Health [R01 DK073368, R35 CA197622, 5T32 GM007231, R01 GM112008, R35 GM127075]
- U.S. Department of Defense [DOD AFOSR FA9550-18-1-0051]
- Office of Naval Research [ONR N00014-17-1-2628]
- Johns Hopkins University
Signaling networks are spatiotemporally organized to sense diverse inputs, process information, and carry out specific cellular tasks. In beta 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 beta 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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