7rec

Publication Abstract from PubMed

Ca(2+)/calmodulin-dependent protein kinase II alpha subunit (CaMKIIalpha) is a key neuronal signaling protein and an emerging drug target. The central hub domain regulates the activity of CaMKIIalpha 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 gamma-hydroxybutyrate (GHB) bind selectively to CaMKIIalpha. By means of a 2.2-A x-ray crystal structure of ligand-bound CaMKIIalpha 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 CaMKIIalpha 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 CaMKIIalpha 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.

GHB analogs confer neuroprotection through specific interaction with the CaMKIIalpha hub domain.,Leurs U, Klein AB, McSpadden ED, Griem-Krey N, Solbak SMO, Houlton J, Villumsen IS, Vogensen SB, Hamborg L, Gauger SJ, Palmelund LB, Larsen ASG, Shehata MA, Kelstrup CD, Olsen JV, Bach A, Burnie RO, Kerr DS, Gowing EK, Teurlings SMW, Chi CC, Gee CL, Frolund B, Kornum BR, van Woerden GM, Clausen RP, Kuriyan J, Clarkson AN, Wellendorph P Proc Natl Acad Sci U S A. 2021 Aug 3;118(31). pii: 2108079118. doi:, 10.1073/pnas.2108079118. PMID:34330837^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.