Ion-Channel Modulators: More Diversity Than Previously Thought

• Published in: Chembiochem : a European journal of chemical biology Vol. 12; no. 12; pp. 1808 - 1812
• Main Authors: Dilly, Sébastien, Lamy, Cédric, Marrion, Neil V., Liégeois, Jean-François, Seutin, Vincent
• Format: Journal Article Web Resource
• Language: English
• Published: Weinheim WILEY-VCH Verlag 16.08.2011; WILEY‐VCH Verlag; Wiley-VCH Verlag Gmbh
• Subjects: allosteric mechanisms; Allosteric Regulation - physiology; Allosteric Site; Amino Acid Sequence; Apamin - chemistry; Apamin - metabolism; Apamin - pharmacology; Binding Sites; Biodiversity; Calcium - metabolism; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channels - chemistry; Calcium Channels - metabolism; drug action; Human health sciences; Humans; Ion Channel Gating; ion channels; Ion Transport - physiology; ligand effects; Membrane Potentials; Models, Molecular; Molecular Sequence Data; Pharmacie, pharmacologie & toxicologie; Pharmacy, pharmacology & toxicology; pore modulators; Potassium - metabolism; Potassium Channel Blockers - chemistry; Potassium Channel Blockers - metabolism; Potassium Channel Blockers - pharmacology; Potassium Channels, Calcium-Activated - chemistry; Potassium Channels, Calcium-Activated - metabolism; Potassium Channels, Voltage-Gated - chemistry; Potassium Channels, Voltage-Gated - metabolism; Protein Binding; Protein Conformation; Sciences de la santé humaine; Spider Venoms - chemistry; Spider Venoms - metabolism; Spider Venoms - pharmacology
• ISSN: 1439-4227; 1439-7633; 1439-7633
• DOI: 10.1002/cbic.201100236

Ion‐channel function can be modified in various ways. For example, numerous studies have shown that currents through voltage‐gated ion channels are affected by pore block or modification of voltage dependence of activation/inactivation. Recent experiments performed on various ion channels show that allosteric modulation is an important mechanism for affecting channel function. For instance, in KCa2 (formerly SK) channels, the prototypic “blocker” apamin prevents conduction by an allosteric mechanism, while TRPV1 channels are prevented from closing by a tarantula toxin, DkTx, through an interaction with residues located away from the selectivity filter. The recent evidence, therefore, suggests that in several ion channels, the region around the outer mouth of the pore is rich in binding sites and could be exploited therapeutically. These discoveries also suggest that the pharmacological vocabulary should be adapted to define these various actions. Channel news: Recent studies on various ion channels have shown that allosteric modulation is an important mechanism for affecting channel function; this indicates that the action of channel modulators is more diverse than initially thought. For example, in SK channels, the “allosteric modulator” apamin was proposed to prevent conduction by binding to the rim of the outer pore (see figure).