Emerging Roles of CREB-Regulated Transcription Coactivators in Brain Physiology and Pathology

Abstract

The brain has the ability to sense, coordinate, and respond to environmental changes through biological processes involving activity-dependent gene expression. cAMP-response element binding protein (CREB)-regulated transcription coactivators (CRTCs) have recently emerged as novel transcriptional regulators of essential biological functions, while their deregulation is linked to age-related human diseases. In the brain, CRTCs are unique signaling factors that act as sensors and integrators of hormonal, metabolic, and neural signals contributing to brain plasticity and brain-body communication. In this review, we focus on the regulatory mechanisms and functions of CRTCs in brain metabolism, lifespan, circadian rhythm, and synaptic mechanisms underlying memory and emotion. We also discuss how CRTCs deregulation in cognitive and emotional disorders may provide the basis for potential clinical and therapeutic applications in neurodegenerative and psychiatric diseases.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…AMPK then phosphorylates and thereby regulates the activities of proteins involved in energy metabolism (glucose transporters and the mTOR pathway), autophagy, and neuronal excitability (Weisová et al, 2009; Ikematsu et al, 2011; Lin and Hardie, 2018; Shah et al, 2017). Calcium is an important signal mediating cellular stress adaptation; Ca 2+ binds to the protein calmodulin, resulting in the activation of kinases that promote the activation of transcription factors including CREB and nuclear factor κB (NF-κB) (Cohen et al, 2015; Saura and Cardinaux, 2017; Snow et al, 2014). One of the Ca 2+ -activated kinases, CamKII, also activates NO synthase.…”

Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

“…This speaks more for a role of CBP in mediating the first transcription wave after CREB becomes activated. CRTC, however, can bind to CREB independent of its phosphorylation status . Moreover, upon an increase in cAMP or Ca 2+ , CRTC is dephosphorylated and transported from synapses to the nucleus .…”

“…CRTC, however, can bind to CREB independent of its phosphorylation status . Moreover, upon an increase in cAMP or Ca 2+ , CRTC is dephosphorylated and transported from synapses to the nucleus . One kinase that phosphorylates CRTC to keep it in the cytoplasm is the 5′‐AMP‐activated protein kinase (AMPK), which is involved in regulating energy metabolism depending on adenosine triphosphate/adenosine monophosphate (ATP/AMP) levels .…”

“…This switch in the cofactor might be a simple mechanism for changing gene expression programs. Furthermore, because CRTC can be shuffled from the synapse to the nucleus, it may relay further information required for maintenance.…”

Epigenetic regulation of Fgf1 transcription by CRTC1 and memory enhancement

“…1). More recently, transcription cofactor CRTC1 has emerged as novel transcriptional regulators of essential biological functions, including brain plasticity and memory formation (Escoubas et al, 2017; Saura and Cardinaux, 2017; Uchida and Shumyatsky, 2017). Nuclear-cytoplasmic redistribution of CRTCs is dependent on their activity-regulated phosphorylation status (Altarejos and Montminy, 2011).…”