How the Blind Watchmaker messed around with potassium channels

Alfred Russel Wallace was one of the leading evolutionary thinkers of the 19th century; among his many accomplishments, he is known for the enormous collection of beetles he assembled during his lifetime. Inspired by this impressive collection, the prominent British biologist J.B.S. Haldane is said to have commented that apparently God has an inordinate fondness for beetles. Similarly, from the impressive collection of studies undertaken by Timothy Jegla and his colleagues at Penn State, which uncovered a large number of Shaker family potassium (K⁺) channels across the geological record, one might say that God also had an inordinate fondness for Shaker K⁺ channels.

In addition to identifying this extensive presence of Shaker channels throughout evolutionary history, the Jegla group has uncovered several surprising findings. One of these is that Shaker family K⁺ channels evolved long before the origins of complex nervous systems. K⁺ channels are critical for electrical signaling in the nervous system, so it might be assumed that as more complex animals evolved, Shaker channels evolved alongside the increasing complexity of the nervous system. However, it turns out that they were already present in microscopic single-cell organisms well before the common ancestor of all multicellular animals. An earlier paper from the Jegla group published in the Proceedings of the National Academy of Sciences (Jegla et al., 2024) identified Shaker family channels in choanoflagellates. Choanoflagellates are considered to be the closest single-celled living relatives of animals. As the proposed sister group to Animalia, choanoflagellates serve as the last unicellular ancestor of animals. A study from 2017 suggested that a group of choanoflagellates known as craspedids originated ∼786 Mya in the Cryogenian period (Dohrmann and Wörheide, 2017). Thus, some of the fundamental building blocks for the nervous system were already in place in our protozoan ancestors before the nervous system developed in early animals.

In their current article in JGP, the Jegla lab investigates K⁺ channel types in ctenophores (Simonson et al, 2025), commonly known as comb jellies (Simonson et al., 2024). Ctenophores are considered one of the oldest extant animal lineages, thought to have evolved during the Ediacaran period (Dohrmann and Wörheide, 2017), which spans 96 million years from the end of the Cryogenian period at 635 Mya to the beginning of the Cambrian period at 538.8 Mya, a time of significant evolutionary radiation of animal types. Comb jellies have soft gelatinous bodies with rows of cilia that enable them to swim. These cilia beat in a coordinated fashion, creating a shimmering effect as they move through the water. The phylum Ctenophora contains about 150 recognized species of comb jellies. Unlike jellyfish, which use stinging cells (nematocysts) to capture prey, comb jellies possess tentacles lined with specialized cells called colloblasts, which secrete a sticky substance to trap small organisms like plankton. Comb jellies possess a decentralized nervous system (a nerve net) lacking a centralized brain. This diffuse network of neurons coordinates movement and responses to environmental stimuli. The ctenophore species Mnemiopsis leidyi was known to have a large set of voltage-gated K⁺ channels, but these represented only two channel lineages shared with cnidarians and bilaterians: Kv1-like Shaker family genes (>40 genes) and the EAG family (2 genes). In metazoans, the Shaker family of voltage-gated K⁺ channels is composed of four subtypes: Shaker (Kv1), Shab (Kv2, the Hodgkin–Huxley delayed rectifier), Shaw (Kv3), and Shal (Kv4) (Wei et al., 1990). Interestingly, all of the voltage-gated K⁺ channels in M. leidyi appear to be of the Kv1 subtype. This is unexpected, as there is evidence for Kv2 through Kv4 subtypes in earlier-appearing single-celled choanoflagellates (Jegla et al., 2024), and all four subtypes are present in virtually all extant vertebrate and invertebrate metazoans (Salkoff et al., 1992). However, little was known about the functional diversity of these Kv1 subfamily channels in M. leidyi. To explore this, the Jegla group functionally expressed 16 of the 40+ Mnemiopsis Kv1 channels and found that they encode a diverse array of voltage-gated K⁺ conductances. These include functional orthologs for many classic Shaker family Kv1 through Kv4 subtypes found in cnidarians (jellyfish) and both vertebrate and non-vertebrate metazoans. The expressed Mnemiopsis channels exhibited a wide range of functional properties, varying significantly in activation and inactivation kinetics and voltage activation ranges. Some channels were active at hyperpolarized voltages, while others were active at depolarized voltages. Ctenophores, therefore, appear to have independently evolved much of their voltage-gated K⁺ channel diversity through evolutionary modifications of the single Kv1 subfamily.

The next step is to determine whether the large contingent of ctenophore Kv1-like voltage-dependent K⁺ channels is subdivided into subfamilies analogous to the Kv1 through Kv4 subfamilies in currently existing metazoans (Salkoff et al., 1992). This seems likely, as the alternative, that the subunits of all genes can indiscriminately co-assemble with all others, seems unlikely since it would produce functional chaos. Some preliminary data support the hypothesis of segregation into separate subfamilies (Simonson et al., 2024). Overall, these studies of K⁺ channel evolution from the Jegla group contribute valuable insights into the evolution of complexity in electrical signaling and the conservation and repurposing of key molecular components throughout evolutionary history.