Venom-derived peptides inhibiting Kir channels: Past, present, and future

Inwardly rectifying K⁺ (Kir) channels play a significant role in vertebrate and invertebrate biology by regulating the movement of K⁺ ions involved in membrane transport and excitability. Yet unlike other ion channels including their ancestral K⁺-selective homologs, there are very few venom toxins known to target and inhibit Kir channels with the potency and selectivity found for the Ca²⁺-activated and voltage-gated K⁺ channel families. It is unclear whether this is simply due to a lack of discovery, or instead a consequence of the evolutionary processes that drive the development of venom components towards their targets based on a collective efficacy to 1) elicit pain for defensive purposes, 2) promote paralysis for prey capture, or 3) facilitate delivery of venom components into the circulation. The past two decades of venom screening has yielded three venom peptides with inhibitory activity towards mammalian Kir channels, including the discovery of tertiapin, a high-affinity pore blocker from the venom of the European honey bee Apis mellifera. Venomics and structure-based computational approaches represent exciting new frontiers for venom peptide development, where re-engineering peptide 'scaffolds' such as tertiapin may aid in the quest to expand the palette of potent and selective Kir channel blockers for future research and potentially new therapeutics. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'