GHB analogs confer neuroprotection through specific interaction with the CaMKII alpha hub domain
| Autor: | Geeske M. van Woerden, Christian D. Kelstrup, Emma K. Gowing, Inge S. Villumsen, Anders B. Klein, Birgitte Rahbek Kornum, Christine L. Gee, Nane Griem-Krey, Mohamed A. Shehata, Ulrike Leurs, Rasmus P. Clausen, Stine J. Gauger, Andrew N. Clarkson, Louise Hamborg, Anne Sofie G. Larsen, Chris C. Chi, Robert O. Burnie, Anders Bach, D. Steven Kerr, Jesper V. Olsen, Sara Marie Øie Solbak, Petrine Wellendorph, John Kuriyan, Ethan D McSpadden, Josh Houlton, Stine B. Vogensen, Selina M. W. Teurlings, Bente Frølund, Line B. Palmelund |
|---|---|
| Přispěvatelé: | Neurosciences |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Enzymologic
0301 basic medicine Carboxylic Acids Excitotoxicity Crystallography X-Ray medicine.disease_cause 0302 clinical medicine Neuropharmacology G alpha subunit Crystallography Multidisciplinary Chemistry Biological Sciences Small molecule Neuroprotection Stroke 5.1 Pharmaceuticals Development of treatments and therapeutic interventions Sodium Oxybate excitotoxicity photoaffinity labeling Protein Binding Signal Transduction photothrombotic stroke photothrombotic storke Cyclopentanes Gene Expression Regulation Enzymologic 03 medical and health sciences Protein Domains Ca2+/calmodulin-dependent protein kinase medicine Humans Binding site x-ray crystallography Pharmacology Binding Sites Photoaffinity labeling Neurosciences Brain Disorders HEK293 Cells 030104 developmental biology Gene Expression Regulation HOCPCA X-Ray Calcium-Calmodulin-Dependent Protein Kinase Type 2 Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Leurs, U, Klein, A B, McSpadden, E D, Griem-Krey, N, Solbak, S M O, Houlton, J, Villumsen, I S, Vogensen, S B, Hamborg, L, Gauger, S J, Palmelund, L B, Larsen, A S G, Shehata, M A, Kelstrup, C D, Olsen, J V, Bach, A, Burnie, R O, Kerr, D S, Gowing, E K, Teurlings, S M W, Chi, C C, Gee, C L, Frølund, B, Kornum, B R, van Woerden, G M, Clausen, R P, Kuriyan, J, Clarkson, A N & Wellendorph, P 2021, ' GHB analogs confer neuroprotection through specific interaction with the CaMKII alpha hub domain ', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 31 . https://doi.org/10.1073/pnas.2108079118 Proceedings of the National Academy of Sciences of the United States of America, 118(31):e2108079118. National Academy of Sciences Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, vol 118, iss 31 |
| ISSN: | 0027-8424 |
| DOI: | 10.1073/pnas.2108079118 |
| Popis: | Significance GHB is a natural brain metabolite of GABA, previously reported to be neuroprotective. However, the high-affinity binding site for GHB has remained elusive for almost 40 y. We here unveil CaMKIIα, a highly important neuronal kinase, as the long-sought-after GHB high-affinity target. Via a specific interaction within the central hub domain of CaMKIIα, GHB analogs act to stabilize the hub oligomer complex. This interaction potentially explains pronounced neuroprotective effects of GHB analogs in cultured neurons exposed to a chemical insult and in mice exposed to ischemia. The postischemic treatment effects of GHB analogs underline these compounds as selective and high-affinity potential drug candidates and CaMKIIα as a relevant pharmacological target for stroke therapy. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|