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Expression and functional characterization of PEA‐15 within the suprachiasmatic nucleus
Author(s) -
Wheaton Kelin,
Queiroz Lucas Sales,
Sullivan Kyle,
Obrietan Karl,
Hoyt Kari
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.813.4
Subject(s) - suprachiasmatic nucleus , biology , mapk/erk pathway , circadian rhythm , microbiology and biotechnology , circadian clock , neuroscience , protein kinase a , effector , scaffold protein , hypothalamus , kinase , signal transduction
The circadian (24 hour) timing system regulates the functional features of most, if not all, physiological process. As such, disruption of the circadian timing system has been shown to have profound negative effects on health, cognition, and to contribute to an array of disease states. Central to the mammalian circadian timing system is the suprachiasmatic nucleus (SCN) of the hypothalamus. This brain structure (often referred to as the ‘master clock’) generates timing cues that coordinates the phasing and amplitude of oscillator populations found throughout the brain, and in peripheral organ systems, such as the liver, lungs and heart. Notably, phasing of the SCN is tightly regulated by photic input signals that are relayed from the retina. The p44/42 mitogen‐activated protein kinase (MAPK) pathway has been shown to be a critical component of the SCN timing system and to function as a key route through which the photic input resets the clock. Here, we investigated cellular mechanisms that regulate ERK (the key effector kinase of the MAPK pathway) phosphorylation and its cellular localization within the SCN. To this end, we examined the expression and function of p hosphoprotein e nhanced in a strocytes ( PEA‐15 ) , a scaffold protein that has been shown to regulate both the activation state of ERK and its subcellular localization. A combination of immunohistochemical labeling and Western analysis methods revealed that PEA‐15 is highly expressed within the mouse SCN. Furthermore, expression profiling detected a significant circadian oscillation in PEA‐15 within the SCN; interestingly, the peak in PEA‐15 expression was antiphase to the well‐characterized circadian oscillation in ERK activity. Photic stimulation of mice led to a significant increase in PEA‐15 phosphorylation at serine‐104, an event that is responsible for the dissociation of ERK from PEA‐15. Consistent with this, co‐immunoprecipitation of ERK and PEA‐15 from SCN lysates revealed that PEA‐15 is directly bound to ERK, and that photic stimulation triggers the dissociation of ERK from PEA‐15. Together, these data reveal that, 1) PEA‐15 is expressed in the SCN, 2) PEA‐15 expression is under the control of the circadian timing system, and 3) PEA‐15 regulates signaling via the MAPK pathway. Given that MAPK signaling is a key regulator of the clock timing system, the data reported here raise the prospect that PEA‐15 could play a key role in modulating the functionality of the SCN timing system. Ongoing work is focused on an examination of potential mechanism by which PEA‐15 affects the timing properties of the SCN. Support or Funding Information This work was supported by NIH MH103361.