GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain

Research output: Contribution to journalJournal articleResearchpeer-review

  • Ulrike Leurs
  • Anders B. Klein
  • Ethan D McSpadden
  • Josh Houlton
  • Inge S Villumsen
  • Stine B Vogensen
  • Louise Hamborg
  • Line B Palmelund
  • Anne Sofie G. Larsen
  • Mohamed A Shehata
  • Christian D Kelstrup
  • Robert O Burnie
  • D Steven Kerr
  • Emma K Gowing
  • Selina M W Teurlings
  • Chris C Chi
  • Christine L Gee
  • Geeske M van Woerden
  • John Kuriyan
  • Andrew N Clarkson

Ca2+/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα) is a key neuronal signaling protein and an emerging drug target. The central hub domain regulates the activity of CaMKIIα by organizing the holoenzyme complex into functional oligomers, yet pharmacological modulation of the hub domain has never been demonstrated. Here, using a combination of photoaffinity labeling and chemical proteomics, we show that compounds related to the natural substance γ-hydroxybutyrate (GHB) bind selectively to CaMKIIα. By means of a 2.2-Å x-ray crystal structure of ligand-bound CaMKIIα hub, we reveal the molecular details of the binding site deep within the hub. Furthermore, we show that binding of GHB and related analogs to this site promotes concentration-dependent increases in hub thermal stability believed to alter holoenzyme functionality. Selectively under states of pathological CaMKIIα activation, hub ligands provide a significant and sustained neuroprotection, which is both time and dose dependent. This is demonstrated in neurons exposed to excitotoxicity and in a mouse model of cerebral ischemia with the selective GHB analog, HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid). Together, our results indicate a hitherto unknown mechanism for neuroprotection by a highly specific and unforeseen interaction between the CaMKIIα hub domain and small molecule brain-penetrant GHB analogs. This establishes GHB analogs as powerful tools for investigating CaMKII neuropharmacology in general and as potential therapeutic compounds for cerebral ischemia in particular.

Original languageEnglish
Article numbere2108079118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number31
Number of pages9
Publication statusPublished - 2021

ID: 275727076