SRC3 acetylates calmodulin in the mouse brain to regulate synaptic plasticity and fear learning.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Protein acetylation regulates cellular functions, but nonhistone protein acetylation in synaptic plasticity and learning is understudied.
• Calmodulin (CaM) is crucial for synaptic plasticity, including long-term potentiation (LTP), but the specific enzymes acetylating CaM remain unidentified.

Purpose of the Study:

• To identify the lysine acetyltransferase (KAT) responsible for CaM acetylation.
• To investigate the role of CaM acetylation in synaptic plasticity and learning.

Main Methods:

• HEK293 cell-based screening to identify KATs.
• Co-immunoprecipitation and in vitro acetylation assays to confirm SRC3-CaM interaction and acetylation.
• In vivo studies using pharmacological inhibition and genetic downregulation of SRC3 in mice.
• Assessment of synaptic plasticity and contextual fear learning in mouse models.
• Rescue experiments using a mutant CaM (3KQ-CaM) mimicking acetylation.

Main Results:

• Steroid receptor coactivator 3 (SRC3) was identified as the primary KAT for CaM.
• SRC3 interacts with and acetylates CaM in a manner dependent on calcium (Ca²⁺) and NMDA receptor activity.
• Inhibition or downregulation of SRC3 impaired CaM acetylation, synaptic plasticity, and contextual fear learning in mice.
• A CaM mutant mimicking acetylation (3KQ-CaM) rescued the deficits caused by SRC3 inhibition.

Conclusions:

• SRC3 directly acetylates CaM, playing a critical role in regulating synaptic plasticity and learning.
• CaM acetylation by SRC3 is a novel mechanism influencing neuronal function and behavior.
• Targeting the SRC3-CaM pathway may offer therapeutic strategies for cognitive disorders.