The Basics of ASICs

Acid Sensing Ion Channels (ASICs) are homo or heterotrimeric receptors which are activated by protons near the physiological range. Each subunit is roughly 500 amino acids with intracellular N and C termini, two transmembrane domains and a large extracellular domain which houses the proton sensors. In humans and rodents there are 4 ASIC genes which give rise to at least 6 different subunits. ASIC1a is widely expressed throughout the central and peripherial nervous system as well as other tissues. In many ways it is the ‘prototypical’ and best studied ASIC and the only one for which we presently have structural data. ASIC1b is a slightly lower affinity version of ASIC1a and is largely restricted to the peripheral nervous system. ASIC2a and b are also widely expressed and are the lowest affinity subunits, requiring pH’s around 4 or lower to maximally activate the channel. ASIC3 is the found mainly in the peripheral nervous system. It is the kinetically fastest of the bunch and has, perhaps, the most interest as a drug target given its role in pain sensation. ASIC4 does not respond to protons nor seemingly heteromerize with other ASICs. It’s function is unknown.

ASICs respond to protons in two general ways. Low concentrations of protons, around pH 7.4 or 40 nM, tend to inhibit ASICs without detectable activation in a process known as steady-state inactivation or desensitization (SSD). Higher concentrations, around 1 to 10 uM or pH 6 to 5, drive the channel to a Na+ selective open state. In the continued presence of protons ASICs undergo an additional conformational change, entering into a desensitized state. Protons activate ASICs via certain protonatable residues distributed in the extracellular domain. While we are still learning the mechanisms at play it seems that a cluster of acidic residues in the pocket the thumb and finger domains, as well as some in the palm domain, are especially important for driving activation and desensitization.