Hot Topics: Exciting Times for Ion Channel Pharmacology

Whilst life is always exciting as an ion channel pharmacologist, the last few months have been particularly so, with a large number of publications showing structures of ion channels with regulatory molecules bound to them. In just the last month, the journal, Science, has published several such papers. Three of these concern voltage-gated sodium channels (NaV1.2, NaV1.7) and the binding of potent and selective toxins from animals [1-3]. Another reveals the structure of the primary human cooling and menthol sensor channel TRPM8 bound to synthetic cooling and menthol-like compounds [4].

In the most recent paper [5], Schewe and colleagues extend their outstanding work on selectivity-filter gating of K2P potassium (K) channels (Schewe et al. (2016). Cell. PMID: 26919430), to identify a binding site for negatively charged activators of these channels (styled the “NCA binding site”). Activators which bind to this site open a number of different K2P channels (e.g. K2P2.1 (TREK-1) and K2P10.1 (TREK-2)) and several other potassium channels such as hERG channels (KV11.1) and BKCa channels (KCa1.1), all of which are gated at their selectivity filter. This is exciting, because it is notoriously difficult to design, or even identify, activator compounds for ion channels. This work together with the identification of a separate “cryptic binding site” for K2P channel activators (PMID: 28693035) opens possibilities for rationale design of activator compounds targeting these binding sites, which would provide potential novel therapeutic approaches for the treatment of several conditions including chronic pain, arrhythmias, epilepsy and migraine (PMID: 30573346).

One potential problem, identified by Schewe et al, is the promiscuity of the NCA binding site across several K channel families. However, there are enough structural differences in the region around the NCA-binding site between the channel types to overcome this. Provocatively, Schewe et al even suggest that the simultaneous activation of several different K channel types at once may even be advantageous in certain acute conditions such as ischemic stroke and status epilepticus.

Comments by Alistair Mathie (@AlistairMathie) and Emma L. Veale (@Ve11Emma), The Medway School of Pharmacy

(1) Clairfeuille T et al. (2019). Structural basis of α-scorpion toxin action on Nav channels. Science, pii: eaav8573. doi: 10.1126/science.aav8573. [PMIDs:30733386].

(2) Shen H et al. (2019). Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science, pii: eaaw2493. doi: 10.1126/science.aaw2493. [Epub ahead of print]. [PMIDs:30765606].

(3) Pan X et al. (2019). Molecular basis for pore blockade of human NaNa+ channel Nav1.2 by the μ-conotoxin KIIIA. Science, pii: eaaw2999. doi: 10.1126/science.aaw2999. [Epub ahead of print]. [PMIDs:30765605].

(4) Yin Y et al. (2019). Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel. Science, pii: eaav9334. doi: 10.1126/science.aav9334. [Epub ahead of print]. [PMIDs:30733385].

(5) Schewe M et al. (2019). A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels. Science, 363(6429):875-880. doi: 10.1126/science.aav0569.. [PMIDs:30792303].


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