Kalienkova Lab

1. Acid sensing ion channels in physiological context

Acid sensing ion channels (ASICs) are broadly expressed in the nervous system and are implicated in pain processing, long term potentiation, memory and learning. Once activated in response to extracellular acidification, the channels carry an excitatory Na⁺ influx. ASICs are linked to several pathological conditions, such as neurodegeneration, neuronal injury in ischemic stroke, and glioblastoma cell migration. Therefore, ASICs are emerging as promising yet understudied drug targets in several pathological conditions. Interestingly, ASICs are modulated by various animal toxins and endogenous neuropeptides, sparking substantial interest in peptides and small protein binders as potential ASIC modulators.

Developing drugs and therapeutics targeting ASICs is challenging for several reasons. Firstly, there are six ASIC variants found in mammals (ASIC1a/b, ASIC2a/b, ASIC3 and ASIC4), which are thought to form homo- and heterotrimers. Homomeric and heteromeric ASICs differ in their sensitivity to protons, their permeability to different ions, and in their response to modulators such as small molecules. However, our knowledge of ASIC structure and function is rather limited to homomeric ASIC1a channels, and the structural basis of varied properties in heteromeric assemblies remains elusive. Additionally, membrane proteins are often regulated by auxiliary subunits and the surrounding lipids. To date, little is known about endogenous interaction networks of ASICs. Targeting ASICs requires a thorough understanding of ASIC function in their physiological context, which is presently lacking, including the differences between homo- and heteromeric channels, the effect of the regulatory interaction partners, and of the lipid environment.