Abstract

Ion channels play a vital role in normal biological functions and are linked to numerous pathophysiological conditions. TRPC3 (transient receptor potential channel) is a non-selective calcium-permeable channel that belongs to the TRPC family within the larger TRP superfamily of cation channels. This receptor-operated ion channel is highly expressed in Purkinje cells of the cerebellum where it is activated by endogenous diacylglycerol (DAG) ([1]). Within these cells TRPC3 co-localises with, and is subsequently activated via, the metabotropic glutamate receptor subtype 1 (mGluR1) indicating a clear role in synaptic transmission, notably slow excitatory post-synaptic currents (sEPSC) ([2]), and in determining intrinsic physiological properties of Purkinje cells (reference: PMID 31486767). In genetically modified mice, the absence or dysfunction (gain-of-function) of TRPC3 leads to impairment of normal Purkinje cell function resulting in a cerebellar ataxia phenotype (reviewed in [3]). Many spinocerebellar ataxias (SCAs) are believed to share common molecular mechanisms including aberrant glutamate and calcium signalling. Consistent with this idea, both mGluR1 and TRPC3 have been genetically linked to cerebellar ataxia; SCAR13 ([4, 5]) and SCA41 ([6]), respectively. Together, these findings underscore the importance of mGluR1-TRPC3 signalling for proper Purkinje cell calcium homeostasis and cerebellar function. It is therefore reasonable to hypothesise that blocking the TRPC3 channel would be beneficial for the treatment of cerebellar ataxia.

Here we report on the outcome of a recent collaboration with the University of Oxford focussed on the identification and validation of tractable chemistry series active against TRPC3. A number of cell-based assays were utilised and developed within GSK to deliver on this objective. In addition, tool compounds were also shared to help validate the models established by the Oxford group thereby expanding research within this field.

References
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