Brain mechanisms of GHB and GABAergic signalling in the Wellendorph Lab
Our lab is devoted to understanding brain mechanisms involving the inhibitory neurotransmitter GABA (γ-aminobutyric acid) and its metabolite GHB (γ-hydroxybutyric acid). We use biochemical and pharmacological analyses in cells, tissues
A main focus is to dissect the functional role of the calcium/calmodulin-dependent protein kinase 2 alpha (CaMKIIa) which we have uncovered as the long-sought-after high-affinity binding site for GHB in the mammalian brain. This involves dissecting molecular mechanisms using highly selective compounds generated in-house, and investigating their potential therapeutic potential in e.g. acute brain injury.
Another focus area is GABAA receptors and their role in brain excitability governed by tonic inhibition using novel ligands and pharmacological assays.
We also work on structural and pharmacological aspects of SLC6A GABA and glycine transporters including how to inhibit them in novel ways.
The Wellendorph lab is involved in severeal innovation activities:
- Exploring novel inhibitors of the nutrient amino acid transporter SLC6A17 (invention filed)
- Development of novel GABA-A receptor negative allosteric modulators for treatment of absenze epilepsy (patent pending)
Both projects are supported by Proof-of-Concept grants from UCPH Lighthouse
Disclosure statement: Prof. Wellendorph is co-founder and CSO of Ceremedy Ltd.
- Identification of the ubiquitous neuronal signalling molecule CaMKIIα as the physiological target for GHB
- Demonstration of the potential effect of GHB analogues in ischemic stroke
- Identification of novel ligands for extrasynaptic GABAA receptors
- Structure-function of GABA transporters
Linked articles:
1A)
Leurs U, Klein AB, McSpadden ED, Griem-Krey N, Solbak SMØ, 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 S, Gowing EK, Teurlings SMW, Chi CC, Gee CL, Frølund B, Kornum BR, van Woerden GM, Clausen RP, Kuriyan J, Clarkson AN & Wellendorph P (2021). GHB confers neuroprotection through specific interaction with the CaMKIIα hub domain. Proc. Natl. Acad. Sci USA 118 No 31 e2108079118. https://doi.org/10.1073/pnas.2108079118
1B)
Wellendorph P, Gauger SJ, Andersen JV, Kornum BR, Solbak SMO, Frølund B. Pharmacol Rev. (2025). International Union of Basic and Clinical Pharmacology. CXX. Y-Hydroxybutyrate protein targets in the mammalian brain – beyond classic receptors. 77(4):100064. https://doi.org/10.1016/j.pharmr.2025.100064
2)
Griem-Krey N, Clarkson AN, Wellendorph P. CaMKIIa as a promising drug target for ischemic grey matter (2022). Brain Sci. 29;12(12):1639. doi: 10.3390/brainsci12121639
3)
Falk-Petersen CB, Rostrup F, Löffler R, Buchleihtner S, Harpsøe K, Gloriam D, Frølund B, Wellendorph P (2021). Molecular determinants underlying delta selective compound 2 activity at d-containing GABAA receptors. Mol. Pharmacol. 100(1), 46-56. doi: 10.1124/molpharm.121.000266
Free e-prints
4)
Shahsavar A & Wellendorph P (2023). GABA transport cycle: Beyond a GAT feeling. Nat. Struct. Mol. Biol. DOI: 10.1038/s41594-023-01032-5
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