Discovery of novel ion channel modulators in herbal medicines

Human species' use of plants as medicines dates back to Paleolithic times. There remain many botanical medicine secrets still to unlock, but we are now against the clock, as our exploitation of the planet reduces biodiversity and with it the natural apothecary upon which we have relied for so long.
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Discovery of novel ion channel modulators in herbal medicines
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"There's rosemary, that's for remembrance." from Hamlet (William Shakespeare).

Preface
There is increasing evidence being uncovered of the long history of human use of plants as medicines, as far back as the Paleolithic period, also supported from an evolutionary perspective by medicinal use of plants by today's non-human primates.  We continue to be avid consumers of botanical medicines, either as traditional medicines or plant-derived drugs - even if when we pick up our prescription drugs, we might be unaware of their botanical origins, which are typically not advertised. Estimates vary widely but perhaps 40% of modern western medicines currently in use are from plants - either directly or made from compounds derived from plant compounds. 

For almost 30 years I have been researching the physiology and pharmacology of voltage-gated potassium (Kv) channels - membrane proteins that open in response to cell membrane depolarization to permit controlled diffusion of K+ ions across the cell membranes - a crucial mechanism by which cells control their excitability and other physiological processes. Six years ago, Dr. Rian Manville (at the time a postdoctoral fellow in my lab) was searching for novel pharmacological modulators of Kv channels from the KCNQ subfamily; my lab had previously discovered that potassium channels can form physical complexes with sodium-coupled solute transporters (which we dubbed "chansporters") and Dr. Manville was interested in finding new ways to probe chansporter structure-function, following on from his first paper in this area. He discovered that mallotoxin (rottlerin) is an agonist of KCNQ2/3, a heteromeric Kv channel that is thought to be the primary molecular correlate of the neuronal M-current, which is an important regulator of neuronal excitability, and mutations in which cause epileptic encephalopathy. When we realized that mallotoxin is found in Mallotus oppositifolius, a plant used in several African countries as a folk medicine anticonvulsant, we were hooked on the idea of discovering novel ion channel modulators from plants, both learning from and helping to explain the molecular basis for the ethnobotanical medicine practices of indigenous peoples.

As it turned out, mallotoxin was an ineffective anticonvulsant, but when we combined it with isovaleric acid, which is also present in Mallotus oppositifolius, their synergistic opening effects on KCNQ2/3 translated into anticonvulsant efficacy in a mouse model, explaining folk medicine usage of the plant.   After that, studying the isovaleric acid structure one night, I realized that it resembles that of GABA, which led us to the discovery that GABA activates KCNQ2/3 channels by direct binding, the first such example for a neurotransmitter with any voltage-gated ion channel.

After these initial discoveries, we took it upon ourselves to collect plants or their extracts from a variety of sources - native Californian plant nurseries, supermarkets, herbal medicine suppliers, Native American botanical medicine stores, and lands in California and elsewhere for which we could obtain permits to collect plants for research purposes. This phase is still ongoing.

The groundwork

About five years ago, as part of our drive to collect plants wherever we could legally obtain them, I looked at what was available in my garden. Rosemary (Salvia rosmarinus) is often used by landscapers in Southern California because it thrives in the conditions here, provides year-round greenery as it is an evergreen shrub, and it has attractive blue flowers and a pleasant aroma.  

rosemary plant
Rosemary plant from the author's garden

Rosemary is also excellent as a kitchen herb for a variety of culinary uses, and enjoys a rich and storied history as a botanical medicine. This includes multiple purported neurological benefits, such as being a memory aid, hence Shakespeare's mention in Hamlet; a recurring theme in traditional medicine is that of ceremony blending with treatment, and rosemary was once carried at funerals and placed onto coffins during burials to ensure the dead would be remembered, while rosemary consumption itself was also believed to aid memory and cognition, an hypothesis currently being tested. 

AI rendition of William Shakespeare holding a bouquet of rosemary

My children collected aerial parts from the rosemary in my garden, separated them into flowers, leaves, and stems, and then I took the rosemary samples to the lab for future analysis. Dr. Manville found some interesting activity with various KCNQ channel combinations, but without a molecular mechanism in sight, the project remained a work in progress for several years while we pursued other seemingly more interesting directions with other plants.

The discovery

After a hiatus from the rosemary project and the lab, Dr. Manville returned determined to find what in rosemary had such interesting effects on KCNQ channels, and he started screening compounds known to be made by the plant. Relatively quickly, he discovered that carnosic acid, a phenolic diterpene that is one of the better-represented constituents of rosemary, was a weak KCNQ2/3 opener but a phenomenal KCNQ3 opener - inducing a massive -62 mV shift in the midpoint voltage dependence of KCNQ3 activation, and this formed the basis for the current Communications Biology paper.

Screening of rosemary compounds on KCNQ3; Manville et al., 2023

What is remarkable about carnosic acid, especially given that it is a natural product, is its combination of efficacy and KCNQ isoform selectivity - it is arguably the most efficacious compound discovered to date that can also discern so well between KCNQ3/5 and KCNQ2/3, and also between KCNQ2 and KCNQ3. The heteromer selectivity arises because its inability to open KCNQ2 dominates in KCNQ2/3 heteromers, while its ability to open both KCNQ3 and KCNQ5 facilitates impressive efficacy in KCNQ3/5 opening. Remarkably, none of the close carnosic acid derivatives we purchased or synthesized were able to open KCNQ3 with anywhere near the efficacy of carnosic acid itself; one wonders if its KCNQ-opening ability is a plant evolutionary adaptation, e.g., for modulating a KCNQ-like channel in insects or other herbivores, to alter their behavior.

The future: food for thought

Now that we have unearthed the remarkable ability of rosemary and carnosic acid to open some KCNQ isoforms, we are hotly pursuing mechanisms and potential uses, using ethnobotanical knowledge as a guide. More generally, we continue to collect plants from a variety of sources and locales and use both manual and high-throughput screening to discover effects on Kv channels that might lead to future drugs, while also uncovering the molecular basis of traditional medicines, for neurological disorders and many other conditions.

Rosemary: food for thought

Our experience thus far has been that the malleability of Kv channel activity in response to plant metabolites, combined with the influential roles of Kv channels in a wide variety of tissues and cell types (not just excitable cells!) suggest they represent an important target for botanical medicines. Sadly, destructive deforestation activities, aggressive monoculturing of commercial crops, and climate change, could one day spell disaster for plant diversity on our planet. With every species that disappears, so disappears a potential cure for cancer, heart disease, Alzheimer's disease, epilepsy, etc., and in addition, our food security is further weakened.  Even if only for selfish reasons, as a member of a genus with a long history of usage of plants as medicine and food, we should strive to address and reverse climate change and unsustainable farming and logging practices, before we reach the point of no return.

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