New research from the University of Toronto Mississauga identifies the GRK2 protein as a key regulator of the body’s circadian clock and highlights potential directions for treating jet lag and fatigue from shift work.
The study, published in Cell Reports, was led by Hai-Ying M. Cheng of the Department of Biology with graduate students Neel Mehta, Arthur H. Cheng, Lucia Mendoza Viveros and postdoctoral fellow Cheng-Kang Chiang among the authors. Their work examines how GRK2 influences the molecular machinery of the brain’s master clock, offering insights into clock speed, amplitude, and re-entrainment following changes in environmental time cues.
The suprachiasmatic nucleus (SCN) in the hypothalamus functions as the brain’s internal master clock, generating circadian rhythms that synchronize physiology and behaviour with daily light-dark cycles. Mehta explains that circadian clocks must continually re-adjust to remain aligned with environmental time; disruptions in this alignment produce jet lag or the chronic desynchrony often experienced by shift workers.
To explore the molecular regulation of the SCN, the research team focused on G-protein-coupled receptor kinase 2 (GRK2), a protein previously best known for roles in cardiac signaling. Using mouse models—whose SCN clock is comparable to humans—the investigators compared normal mice with animals lacking GRK2. GRK2-deficient mice showed a lengthened behavioral circadian period, reduced responsiveness to light cues, and a slower recovery from experimentally induced jet lag.
At the molecular level, the study examined interactions between GRK2 and PERIOD proteins (PERIOD1 and PERIOD2), which are central components of the cellular circadian clock. The researchers found that GRK2 suppresses transcription of the mPeriod1 gene and inhibits nuclear trafficking of both PERIOD1 and PERIOD2 proteins. Because PERIOD proteins must enter the nucleus to avoid degradation and to participate in feedback loops that set clock timing, impaired trafficking disrupts normal clock function. GRK2 was also shown to bind physically to PERIOD1/2 and to promote phosphorylation of PERIOD2 at a specific residue (Ser545), a modification that may influence PERIOD protein localization and stability.
Collectively, these findings reveal multiple mechanisms by which GRK2 fine-tunes circadian clock properties: it adjusts clock speed (period), modifies amplitude, and affects entrainment—how the internal clock synchronizes to external light-dark cycles. By modulating PERIOD transcription, post-translational modification, and nuclear trafficking, GRK2 emerges as a significant regulator of circadian timing at both transcriptional and post-translational levels.
The implications of this work extend beyond basic clock biology. Understanding the molecular regulators that determine how rapidly and robustly the clock adjusts to environmental cues could inform targeted strategies for minimizing the effects of jet lag and managing the health consequences of shift work. The authors suggest that further research could explore whether manipulating GRK2 activity or related pathways helps accelerate re-entrainment after time zone shifts or reduces chronic circadian disruption in occupational settings.
Source: Elaine Smith – University of Toronto Mississauga
Image Credit: University of Toronto Mississauga
Original Research: “GRK2 Fine-Tunes Circadian Clock Speed and Entrainment via Transcriptional and Post-translational Control of PERIOD Proteins” by Neel Mehta, Arthur H. Cheng, Cheng-Kang Chiang, Lucia Mendoza-Viveros, Harrod H. Ling, Abhilasha Patel, Bo Xu, Daniel Figeys, and Hai-Ying M. Cheng. Published online August 13, 2015 in Cell Reports (doi:10.1016/j.celrep.2015.07.037).
Abstract (concise summary)
GRK2 Fine-Tunes Circadian Clock Speed and Entrainment via Transcriptional and Post-translational Control of PERIOD Proteins
Key findings
- Loss of GRK2 alters light-induced entrainment and delays recovery from jet lag.
- GRK2 deficiency increases circadian amplitude and lengthens the behavioral period.
- GRK2 suppresses mPeriod1 gene transcription and impairs nuclear trafficking of PERIOD1 and PERIOD2 proteins.
- GRK2 physically associates with PERIOD1/2 and promotes phosphorylation of PERIOD2, actions that likely affect PERIOD localization and function.
Summary
The pacemaker properties of the suprachiasmatic nucleus depend on mechanisms that control clock protein expression and behavior. This study demonstrates that GRK2 is a modulator of SCN properties: mice lacking Grk2 display phase-dependent changes in light-induced entrainment, slower recovery from jet lag, and an extended behavioral rhythm. At the tissue level, Grk2 ablation increases SCN rhythmic amplitude and decreases intrinsic period. Mechanistically, GRK2 represses transcription of the mPeriod1 gene, limits PERIOD1/2 nuclear entry, interacts with PERIOD proteins, and promotes PERIOD2 phosphorylation at Ser545. These combined transcriptional and post-translational effects identify GRK2 as an important regulator of circadian clock speed, amplitude, and entrainment.