Model prokaryotic potassium channels: Predictive power and relevance to eukaryotic channels.

Prokaryotic ion channels have played a foundational role in defining the structural and mechanistic principles of potassium channel function. Beyond their historical importance, we argue that bacterial channels retain, even today, predictive power for understanding the regulation of complex eukaryotic channels. Their reduced architectural complexity, high expression yields, and compatibility with controlled functional and structural assays enable direct correlations between conformational states and activity that remain difficult to achieve for many eukaryotic channels. While numerous prokaryotic ion channels across different families have advanced our understanding of membrane protein structure and function, we focus here on a subset of bacterial potassium channels-KcsA, MthK, and SthK-as experimentally tractable model systems. Using these examples, we illustrate how prokaryotic models have anticipated conserved mechanisms of permeation, selectivity, bundle crossing and filter gating, ball-and-chain inactivation, and lipid modulation-often years before these processes could be structurally or functionally resolved in eukaryotic homologs. Importantly, insights from prokaryotic channels not only recapitulate known behaviors but also guide hypothesis generation, experimental design, and mechanistic interpretation for eukaryotic systems under otherwise inaccessible conditions. As high-resolution cryo-EM increasingly reveals conformations of complex channels, the ability to test underlying relationships between structure and function becomes paramount. We propose that prokaryotic ion channels serve as valuable predictive biophysical platforms that can bridge atomic-level mechanisms and physiological regulation, continuing to impact how ion channel function is conceptualized and experimentally interrogated.