Developmental change in the electrophysiological and pharmacological properties of acid-sensing ion channels in CNS neurons

Acid-sensing ion channels (ASICs) are proton-gated cation channels that play important roles in the CNS including synaptic plasticity and acidosis-mediated neuronal injury. ASIC1a and ASIC2a subunits are predominant in CNS neurons, where homomultimeric and heteromultimeric channel configurations co-exist. Since ASIC1a and ASIC2a have dramatic differences in pH sensitivity, Ca²⁺ permeability and channel kinetics, any change in the level of individual subunits may have significant effects on the properties and functions of ASICs. Using patch-clamp recording, fluorescent Ca²⁺ imaging and molecular biological techniques, we show dramatic developmental changes in the properties of ASICs in mouse cortical neurons. For example, the amplitude of ASIC currents increases whereas desensitization decreases with neuronal maturation. Decreased H⁺ affinity and acid-evoked [Ca²⁺]_i but increased Zn²⁺ potentiation were also recorded in mature neurons. RT-PCR revealed significant increases in the ratio of ASIC2/ASIC1 mRNA with neuronal maturation. Thus, contributions of ASIC1a and ASIC2a to overall ASIC-mediated responses undergo distinct developmental changes. These findings may help in understanding the precise role of ASICs in physiological and pathological conditions at different developmental stages. Acid-sensing ion channels (ASICs) are a novel family of ligand-gated ion channels activated by protons. Recent studies have demonstrated that activation of ASICs, particularly the calcium-permeable ASIC1a channels, plays an important role in the learning/memory process and in acidosis-mediated neuronal injury. In CNS neurons, ASIC1a and ASIC2a subunits are the major functional subunits where combinations of homomeric and heteromeric channels co-exist. Since ASIC1a and ASIC2a subunits have dramatic differences in their electrophysiological/pharmacological properties, any changes in the levels of individual subunits may have a significant influence on the properties of ASICs and their role in acid signalling. In this study, we demonstrate dramatic developmental changes in the electrophysiological and pharmacological properties of ASICs in CNS neurons, which are probably mediated by the change of expression level of ASIC subunits. Our findings may explain the age-dependent changes in learning/memory and the sensitivity of different age groups to acidosis-mediated neuronal injury.