Acid Sensing Ion Channels (ASIC)
Membrane Transport

ACID SENSIG ION CHANNEL (ASIC 1a)

Acid-sensing ion channels (ASICs) are voltage-independent, proton-activated receptors that belong to the epithelial sodium channel/degenerin family of ion channels and are implicated in perception of pain, ischaemic stroke, mechanosensation, learning and memory.

The structure

The structure of ASIC1 is characterized by subunit of the chalice-shaped homotrimer that is formed by a short amino and carboxy termini, two transmembrane helices, a bound chloride ion and a disulphide-rich, multidomain extracellular region enriched in acidic residues and carboxyl-carboxylate pairs within 3.0Å, suggesting that at least one carboxyl group bears a proton. Electrophysiological studies on aspartate-to-asparagine mutants confirm that these carboxyl-carboxylate pairs participate in proton sensing. Between the acidic residues and the transmembrane pore lies a disulphide-rich ‘thumb’ domain poised to couple the binding of protons to the opening of the ion channel, thus demonstrating that proton activation involves long-range conformational changes.

PubMed - Structure of an Acid-sensing Ion Channel 1 at 1.9 Å Resolution and LOW PH

ASICs: background

Significant progress has been made in understanding the structure and function of ASICs at the molecular level. Studies aimed at clarifying their physiological importance have suggested roles for ASICs in pain, neurological and psychiatric disease, in fact recent findings link these channels to physiology and disease.
Acid-evoked currents were first observed in neurons in the early 1980s. In 1997, a protein producing a similar acid-gated current was cloned and identified as an acid-sensing ion channel (ASIC). This protein was closely related to a previously cloned member of the degenerin–epithelial Na+ channel family (DEG–ENaC family). This and other related channel family members were subsequently found to be pH sensitive and renamed ASICs to reflect their related structure, function and pH sensitivity. We now know that the ASIC family of channel subunits (TABLE 1) is largely responsible for the acid-evoked currents observed in neurons.
- In peripheral sensory neurons, ASICs have been found on cell bodies and sensory terminals, where they have been suggested to be important for nociception and mechanosensation.
- In central neurons, ASICs have been found on the cell body, dendrites and at dendritic spines and have been suggested to contribute to synaptic plasticity.
ASICs are permeable to cations and are activated by extracellular acidosis. They are subject to modulation by extracellular alkalosis, intracellular pH and various other factors. Much of what we know about these channels’ properties comes from expressing recombinant ASIC subunits in heterologous cells. Channels are formed by combinations of ASIC subunits in homotrimeric or heterotrimeric complexes, with different subunits conferring distinct properties (TABLE 1). The amino acid sequences of ASIC subunits are well conserved between species, in fact the mouse ASIC 1a and the human ASIC 1a share over 99% of their amino acid sequence identity. The recently described crystal structure of the chicken ASIC1 homomultimeric channel has shed light on the subunit interactions and, along with sequence homology analyses, has driven numerous structure–function experiments that are revealing how the channels respond to pH and other stimuli. In addition to the non-covalent inter-subunit interactions, disulphide bonds between trimers may also create higher-order complexes and alter channel function.
The channels are activated by protons and other endogenous or exogenous chemicals, it has also been sug¬gested that ASICs respond to mechanical stimuli.
Compared with ASIC 1a, much less is known about the other ASIC subunits in the brain: it is known that ASIC 2a and ASIC 2b are expressed in the brain, but unlike ASIC 1a these subunits are not required for acid-evoked currents in central neurons. However, in the absence of ASIC 1a, ASIC 2 subunits produced a small amount of current in brain neurons in response to very acidic pH (pH 4.0). ASIC 2a and ASIC 2b interact with ASIC 1a and can shift the pH sensitivity, desensitization kinetics and ion selectivity of acid-evoked currents.
The precise mechanisms by which ASICs are activated in the brain remain uncertain, but one potential mechanism might involve protons released during neurotransmis¬sion by acidic (~pH 5.5) neurotransmitter-containing vesicles, also protons generated by other sources, such as localized energy metabolism, might also contribute to ASIC activation.
ASICs most probably influence neuronal function through membrane depolarization, Ca++ entry and through a number of downstream signalling cascades.

PubMed - Acid-sensing ion channels in pain and disease