Modulation of acid-sensing ion channels: molecular mechanisms and therapeutic potential

Abstract

Increases in extracellular proton concentrations, which takes place in physiological conditions such as synaptic signaling and pathological conditions such as tissue inflammation, ischemic stroke, traumatic brain injury, and epileptic seizure, activates a unique family of membrane ion channels; the acid-sensing ion channels (ASICs). All ASICs belong to amiloride-sensitive degenerin/epithelial Na(+) channel superfamily. Four genes encoded at seven sub-units have been identified. ASICs are expressed primarily in neurons and have been shown to play critical roles in synaptic plasticity, learning/memory, fear conditioning, sensory transduction, pain perception, ischemic brain injury, seizure, and other neurological as well as psychological disorders. Although protons are the primary activator for ASICs, the properties and/or level of expression of these channels are modulated dramatically by neuropeptides, di-and polyvalent cations, inflammatory mediators, associated proteins, and protein phosphorylations, etc. Modulation of ASICs can result in profound changes in the activities and functions of these channels in both physiological and pathological processes. In this article, we provide an up to date review on the modulations of ASICs by exogenous agents and endogenous signaling molecules. A better understanding of how ASICs can be modulated should help define new strategies to counteract the deleterious effects of dysregulated ASIC activity.

Keywords: Acid-sensing ion channel; acidosis; modulation; neuron.

Figure 1

Modulation of ASICs by extracellular and intracellular signaling molecules. ASICs are activated by protons and non-proton molecules such as GMQ (for ASIC3 only). Activation of ASIC1a, voltage-gated calcium channels (VGCCs), glutamate receptors (GluRs) and the releases of intracellular Ca²⁺ pools increases intracellular [Ca²⁺]ⁱ. The resulting increase in [Ca²⁺]ⁱ triggers downstream signaling events, including CaMKII activation. ASIC activity is also regulated by interactions with CaMKII, PKA, PKC, AKAP150, calcineurin, PICK1 and possibly other PDZ-domain proteins such as CIPP.