ASICs can form homo- and heterotrimeric complexes. In neurons of the central nervous system (CNS), all isoforms (except ASIC1b) have also been detected, and the ASIC1a isoform is predominant ( Deval and Lingueglia, 2015 Schuhmacher and Smith, 2016). In neurons of the peripheral nervous system (PNS), all isoforms and especially ASIC3 have been found, with the exception of ASIC4. In the mid-1990s, the channels with such properties were cloned and expressed and then got their modern name of “acid-sensing ion channels” ( Waldmann et al., 1997).įour genes encode six isoforms of ASICs in mammals: ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4 ( Wemmie et al., 2006). Indirect confirmation of the existence of these channels was first obtained in the early 1980s, when sodium-selective and rapidly activated and desensitized transient current was detected on mammalian sensory neurons in response to a sharp acidification of the extracellular medium ( Krishtal and Pidoplichko, 1980 Krishtal, 2015). They are of the most sensitive sensors of acidification in the organism. In this review, we only include natural ligands capable of interacting with an acid-sensing ion channels (ASICs).ĪSICs are Na +-selective channels abundantly expressed in neurons of the peripheral and central nervous systems, where they perform an important function in signal transmission associated with a local change in pH. As a result, there is an overabundance of structural and functional information of natural compounds that was not confirmed by cellular target specificity. The modern growth development of genomics, proteomics, and biotechnology make possible successful study of bioactive molecules, even from very rare animals. However, the appearance of effective separation methods provided a significant impetus to the promotion of natural compounds from other organisms on the drug market, since it became possible to remove highly toxic components of venoms. Since ancient times, pharmacy has been based inherently on the discovery, examination, and implementation of bioactive molecules, mainly from plants, for treatment of humans. Natural compounds synthesized by marine and terrestrial inhabitants of three kingdoms (animals, plants, and bacteria) can be considered simultaneously a hazard and a remedy for life quality improvements. The selectivity to different isoforms and variety in the channel modulation mode allow for the appraisal of prospective candidates for the development of new drugs. Without toxins, it would not be possible to obtain data on the mechanisms of ASICs’ functioning, provide detailed study of their pharmacological properties, or assess the contribution of the channels to development of different pathologies. Many of the examples provided in the review demonstrate the undoubted fundamental and practical successes of using natural toxins. In this review, we provide a detailed and comprehensive structural and functional description of natural compounds acting on ASICs, as well as the latest information on structural aspects of their interaction with the channels. However, to date, the search for such molecules has been most effective amongst natural sources, such as animal venoms or plants and microbial extracts. Such bioactive compounds can be synthesized artificially. Ligands of ASICs serve as indispensable tools for these studies. Structural and functional studies of both wild-type and mutant ASICs are essential for human care and medicine for the efficient treatment of socially significant diseases and ensure a comfortable standard of life. Six isoforms of these channels are widely represented in membranes of neuronal and non-neuronal cells, where these molecules are involved in different important regulatory functions, such as synaptic plasticity, learning, memory, and nociception, as well as in various pathological states. 2Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, RussiaĪcid-sensing ion channels (ASICs) are of the most sensitive molecular sensors of extracellular pH change in mammals.
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