Skip to content
DraconiticResearch
Search Sources API
203,203 studies31 sourcesUpdated 54 min ago
Peer-reviewedCC BY 4.0Cells

CaMKK2 in Central Nervous System Disorders: Context-Dependent Signaling and Therapeutic Challenges

  • Jia-Xi Zhang1
  • Yi-Kai Zou1
  • Xian-Guang Lin1
  • Shao-Hua Qi2
  • Jia-Wei Min1,3,4
4 affiliations
  1. 1College of Biomedical Engineering, South-Central Minzu University, Wuhan 430074, China
  2. 2Ting Tsung and Wei Fong Chao Center for BRAIN, Houston Methodist Academic Institute and Weill Cornell Medicine, Houston, TX 77030, USA
  3. 3Hubei Key Laboratory of Medical Information Analysis & Tumor Diagnosis and Treatment, Wuhan 430074, China
  4. 4Key Laboratory of Cognitive Science, State Ethnic Affairs Commission, Wuhan 430074, China
Open at sourceDOICite

Abstract

Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) couples calcium signaling to metabolic, inflammatory, and transcriptional pathways and has been implicated in a broad range of central nervous system (CNS) disorders. However, its effects vary across disease settings, and the mechanisms underlying this context dependence remain poorly defined. This narrative review examines genetic, transcriptomic, biochemical, cellular, and in vivo evidence on the roles of CaMKK2 across CNS disorders, with emphasis on signaling pathways, cell type-specific functions, and implications for therapeutic targeting. CaMKK2-associated pathways influence neurovascular responses, synaptic function, protein homeostasis, inflammation, and tumor progression through signaling networks involving AMPK, CaMK1, CaMK4, and Akt. CaMKK2 can exert distinct, and in some settings opposing, effects depending on cell type, downstream pathway engagement, intervention timing, and pathological context. Pharmacological studies remain limited by incomplete selectivity, insufficient characterization of CNS pharmacokinetics, and context-dependent biological effects. Moreover, much of the mechanistic evidence derives from experimental models, and validated biomarkers for clinical translation remain limited. Overall, CaMKK2 emerges as a context-dependent signaling node linking calcium signaling to metabolic and inflammatory pathways in CNS disorders, with therapeutic potential but substantial challenges for therapeutic translation.

Related

  1. Central Nervous System Reservoirs and HIV Cure: Therapeutic Opportunities and Challenges.
    Thomas A Angelovich, Michael Roche, Paul R Gorry +1
    Current HIV/AIDS reportsPeer-reviewedCC BYFull textMicrobiologyEurope PMC
  2. Context-dependent cGAS–STING signaling in inflammatory bowel disease: cell specificity, lesion state, and therapeutic windows
    Huihui Bian, Wenjing Jin, Yuhong Chen +2
    Frontiers in ImmunologyPeer-reviewedCC BY 4.0Full textImmunologyCrossrefEurope PMCPMC
  3. Context-dependent cGAS-STING signaling in solid tumors: biological determinants, clinical implications, and biomarker-guided therapeutic strategies
    Zhenru Wang, Yuerufei Yu, Ying Zhu
    Frontiers in ImmunologyPeer-reviewedCC BY 4.0Full textImmunologyCrossrefEurope PMCPMCEurope PMC
  4. Focused Ultrasound Neuromodulation of the Central Lateral Thalamus in a Non-Human Primate Model of Disorders of Consciousness
    C. Lybbert, C. Garrett, T. D. Webb +3
    bioRxivPreprintAll rights reservedFull textNeurosciencebioRxiv
  5. Astrocytic GABAergic signaling in perioperative neurocognitive disorders: mechanisms and intervention strategies
    Ting Tang, Xingcen Wang, HuiJuan Huang +2
    Frontiers in neurosciencePeer-reviewedCC BYFull textNeuroscienceEurope PMC

Cite

BibTeXRIS
BibTeX
@article{zhang2026camkk2,
  title = {{CaMKK2 in Central Nervous System Disorders: Context-Dependent Signaling and Therapeutic Challenges}},
  author = {Jia-Xi Zhang and Yi-Kai Zou and Xian-Guang Lin and Shao-Hua Qi and Jia-Wei Min},
  journal = {Cells},
  year = {2026},
  month = nov,
  doi = {10.3390/cells15212012},
  url = {https://www.mdpi.com/2073-4409/15/21/2012},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - CaMKK2 in Central Nervous System Disorders: Context-Dependent Signaling and Therapeutic Challenges
AU  - Jia-Xi Zhang
AU  - Yi-Kai Zou
AU  - Xian-Guang Lin
AU  - Shao-Hua Qi
AU  - Jia-Wei Min
PY  - 2026
DA  - 2026/11/05
JO  - Cells
DO  - 10.3390/cells15212012
UR  - https://www.mdpi.com/2073-4409/15/21/2012
AB  - Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) couples calcium signaling to metabolic, inflammatory, and transcriptional pathways and has been implicated in a broad range of central nervous system (CNS) disorders. However, its effects vary across disease settings, and the mechanisms underlying this context dependence remain poorly defined. This narrative review examines genetic, transcriptomic, biochemical, cellular, and in vivo evidence on the roles of CaMKK2 across CNS disorders, with emphasis on signaling pathways, cell type-specific functions, and implications for therapeutic targeting. CaMKK2-associated pathways influence neurovascular responses, synaptic function, protein homeostasis, inflammation, and tumor progression through signaling networks involving AMPK, CaMK1, CaMK4, and Akt. CaMKK2 can exert distinct, and in some settings opposing, effects depending on cell type, downstream pathway engagement, intervention timing, and pathological context. Pharmacological studies remain limited by incomplete selectivity, insufficient characterization of CNS pharmacokinetics, and context-dependent biological effects. Moreover, much of the mechanistic evidence derives from experimental models, and validated biomarkers for clinical translation remain limited. Overall, CaMKK2 emerges as a context-dependent signaling node linking calcium signaling to metabolic and inflammatory pathways in CNS disorders, with therapeutic potential but substantial challenges for therapeutic translation.
SN  - 2073-4409
ER  -