Neurodegenerative Disease: What Potential Therapeutic Role of Acid-Sensing Ion Channels?

Abstract

Acidic pH shift occurs in many physiological neuronal activities such as synaptic transmission and synaptic plasticity but also represents a characteristic feature of many pathological conditions including inflammation and ischemia. Neuroinflammation is a complex process that occurs in various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. Acid-sensing ion channels (ASICs) represent a widely expressed pH sensor in the brain that play a key role in neuroinflammation. On this basis, acid-sensing ion channel blockers are able to exert neuroprotective effects in different neurodegenerative diseases. In this review, we discuss the multifaceted roles of ASICs in brain physiology and pathology and highlight ASIC1a as a potential pharmacological target in neurodegenerative diseases.

Keywords: ASIC1a; acidosis; neurodegenerative disease; neuroinflammation; pH shift.

FIGURE 1

Acid-sensing ion channel 1a (ASIC1a) structure and the binding sites of its modulators. (A) A schematic view of the ASIC1 subunit highlighting the different domains: finger (purple), knuckle (turquoise), β-ball (orange), palm (yellow), and thumb (blue) and transmembrane domains (red). The binding sites for the different drugs are also indicated. (B) Crystal structure of an ASIC1 subunit obtained from chicken ASIC1 binding Mit-Tx (Baconguis et al., 2014). The domains are colored as in panel A. Readapted from Boscardin et al. (2016).