One way for neurons to communicate with each other is through highly localised changes in brain tissue pH that activate acid-sensing ion channels (ASIC1a). The subtype ASIC1a plays a significant role in detecting low pH and makes essential contributions to learning and memory. However, some of the most prevalent neurological disorders, such as depression, chronic pain, and ischemia, also exhibit brain tissue acidification. Chronic pain alone has a prevalence of 19% in the adult European population, and ischemic stroke imposes a heavy socio-economic burden with currently extremely limited therapeutic options. One determining factor between physiological and pathological activation of ASIC1a appears to be the presence of BigDynorphin (BigDyn), a neuropeptide with physiological roles in circadian rhythm and appetite control. During neurological stress, however, BigDyn levels increase and, together with low tissue pH, activate ASIC1a to an extent that can be toxic to neurons, worsening the outcome of the related disorder.
Targeting the dynorphin–ASIC1a interaction has therefore great therapeutic potential and could present an avenue to design a new generation of ASIC-selective drugs that could treat pain without the typical downsides of opioids or limit neurotoxicity during ischemic strokes. However, its exploitation was hampered by the limited mechanistic insight of the interaction and the lack of methods to directly assess it in detail.
Thus, the project first aimed to establish a protocol using a fluorescence-coupled electrophysiology approach that would allow us to look at the interaction in a cell-based system. In a second step, we then wanted to identify the binding site of dynorphins on ASIC1a and analyse the binding processes under pathological conditions. We anticipate that the information gained from this project will aid the future design of ASIC1a inhibitors with the potential to treat chronic pain and ischemia.
