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.
- 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:
- 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
- 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
- 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
- The Lundbeck Foundation
2019-2024: PI and coordinator of thematic grant GHB-ACTION. Collaborators (co-PIs):
Geeske M. van Woerden
Andrew N. Clarkson
John Kuriyan
Bente Frølund
Birgitte Kornum - Hørslev Foundation
- Independent Research Fund Denmark
- The Novo Nordisk Foundation
2021-2026: PI and coordinator of Hallas-Møller Ascending Investigator grant (aGABAsign)Collaborators (co-PIs):
Margot Ernst
Andrew N. Clarkson
Bente Frølund
Ales Marek
Kristi Kohlmeier
Mike Gibson
2023
Boat trip
2022
Group photo from the December dinner
Team building
2021
Paddle tennis
2019
Escape Room Dec 2019
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