Student Posters 51st Lorne Proteins Conference 2026

Activation of the GABAB Receptor by Conopeptides and Orthosteric Agonists. (#318)

David Safadi 1 2 , Aidan Grosas 1 2 , David J Adams 1 2
  1. Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia
  2. Centre for Cryo-electron Microscopy of Membrane Proteins, University of Wollongong, Wollongong, NSW, Australia

Chronic pain affects more than 30% of the global population1. However, current therapeutic options remain limited and are often associated with significant side effects, highlighting the urgent need for novel analgesics with minimal adverse effects. 

The γ-aminobutyric acid type B receptor (GABABR) is widely expressed throughout the nervous system and plays a central role in regulating pain transmission. GABABR activation inhibits high voltage-activated calcium channels and potentiates G-protein-coupled inwardly rectifying potassium channels, leading to reduced neuronal excitability and attenuation of pain signalling. Additionally, GABABR activation inhibits adenylyl cyclase resulting in decreased intracellular cAMP levels2.

Conopeptides are a diverse family of bioactive peptides derived from the venom of marine cone snails (genus Conus). They represent promising drug scaffolds due to their small size, high target specificity, and structural stability3. A small subset of α-conopeptides, originally characterised as nicotinic acetylcholine receptor antagonists, including Vc1.1, RgIA, and PeIA, exhibit antinociceptive effects through activation of GABABR in animal models of chronic visceral and neuropathic pain4. These peptides are proposed to engage a novel allosteric binding site on the receptor, however, the precise molecular mechanisms underlying GABABR activation remain unresolved5.

Here, we report the effects of conopeptides and orthosteric GABABR agonists on GABABR-mediated modulation of adenylyl cyclase activity and intracellular cAMP levels. Our results reveal distinct signalling profiles for conopeptide versus orthosteric agonist activation of the GABABR. We further outline a framework for the structural characterisation of conopeptide-GABABR interactions, integrating in silico screening using AlphaFold with cryo-EM. Together, these approaches provide a foundation for elucidating the molecular basis of GABABR activation and for guiding the development of novel non-opioid analgesics.

  1. Cohen, S. P., Vase, L. & Hooten, W. M. 2021. Chronic pain: an update on burden, best practices, and new advances. The Lancet, 397, 2082-2097.
  2. Rose, T.R., Wickman, K. 2020. Mechanisms and Regulation of Neuronal GABAB Receptor-Dependent Signaling. In: Vlachou, S., Wickman, K. (eds) Behavioral Neurobiology of GABAB Receptor Function. Current Topics in Behavioral Neurosciences, vol 52. Springer, Cham pp 39-79
  3. Jin, A.-H., Muttenthaler, M., Dutertre, S., Himaya, S. W. A., Kaas, Q., Craik, D. J., Lewis, R. J. & Alewood, P. F. 2019. Conotoxins: Chemistry and Biology. Chemical Reviews, 119, 11510-11549.
  4. Bony, A. R., McArthur, J. R., Finol-Urdaneta R. K. & Adams, D. J. 2022. Analgesic α-conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA(B) receptors and reduce neuroexcitability. Br J Pharmacol, 179, 179-198.
  5. Bony, A. R., McArthur, J. R., Komori, A., Wong, A. R., Hung, A. & Adams, D. J. 2022 Analgesic α-Conotoxin Binding Site on the Human GABAB Receptor. Molecular Pharmacology, 102, 196-208.