Synaptic protein delivery in health and disease / Synthetic cannabinoid receptor agonists: cardiotoxicity linked to hERG potassium channel inhibition

A Snapshot seminar hosted by the School of Physiology, Pharmacology and Neuroscience

Kevin Wilkinson: Synaptic protein delivery in health and disease

Abstract: The extraordinary morphological complexity of neurons presents unique challenges for ensuring that the right proteins are delivered to the right place at the right time. In particular, neuronal membrane trafficking must be highly coordinated to ensure appropriate control of neuronal excitability, synaptic strength, and sensitivity to extracellular ligands and growth cues. Once delivered to the surface, membrane proteins are not static, but exhibit dynamic behaviour through rounds of internalisation and recycling to the cell surface. As such, this recycling pathway represents an important decision step in determining how much of a given membrane protein is expressed on the surface at a particular time. My group are interested in the molecular mechanisms of this decision step, focussing on a protein complex called retromer, and its associated protein SNX27, which are involved in selecting membrane proteins for recycling back to the cell surface. We have shown previously that SNX27-retromer plays a role in the surface delivery of cargo proteins destined for both excitatory and inhibitory synapses, and our preliminary data suggest retromer is an important determinant of inhibitory synaptic drive through regulation of the chloride extruder KCC2. In this talk, I will briefly outline this work so far, and discuss our current interests into how this shared molecular machinery can support appropriate delivery of such functionally diverse cargoes.

Hongwei Cheng: Synthetic cannabinoid receptor agonists: cardiotoxicity linked to hERG potassium channel inhibition

Abstract: Synthetic cannabinoid receptor agonists (SCRAs) are psychotropic drugs, most of which have no clinical indication and are used in non-clinical settings, notably among incarcerated and deprived demographics. SCRA use is associated with significant morbidity and mortality; deaths with these drugs are mostly associated with sudden collapse. Therefore, it is critical to understand the basis for their toxicity. Growing evidence indicates that SCRA use is associated with ECG abnormalities, including QT interval prolongation, indicative of delayed ventricular repolarisation which can increase likelihood of arrhythmia risk. hERG channel inhibition is strongly linked to drug induced long QT syndrome and using in silico approaches we have identified the cardiac hERG potassium channel as a likely target for SCRAs and have predicted ventricular action potential prolongation with these drugs. With funding from the BHF, we have been characterizing effects of SCRAs on hERG channels in vitro over the last 4 months. We have demonstrated that a widely used SCRA 5F-AKB48 inhibits hERG channel current, in line with our in silico predictions. Our initial experimental data suggest that the inhibition has some distinctive features, which are likely to extend understanding of hERG channel pharmacology as well as cardiotoxicity of SCRAs. In my presentation, I will show the data we have obtained so far and outline our future experimental plans.

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