What do human anxiety and moulting insects have in common?

A fear of insects could result in a vicious cycle. T. Nathan Mundhenk. Stills montage by TCUK, CC BY-SA

You might not imagine that those sweaty palms and palpitations that you experience when you are anxious have anything to do with an insect that sheds its skin. But in fact, the proteins that control anxiety in humans and cause insects to shed their skins have a common evolutionary origin.

In research we published in Open Biology, we looked at neuropeptides – the small protein-like molecules that are used by neurons to communicate with one other in the brain and nervous system – and found that one of these, called NGFFFamide, provides the “missing link” that enables us to reconstruct the remarkable evolutionary history of previously unassociated signalling systems in the brain.

Neuropeptides function by binding to receptor proteins on target neurons, which triggers intracellular cascades of signals that ultimately lead to the regulation of a broad range of physiological processes and behaviours.

Morphine: mimicks signal enablers called enkaphalins. Vaprotan, CC BY-SA

Some of the best-known neuropeptides are the enkaphalins, which bind to and activate opioid receptors in the brain and ultimately lead to analgesic-like effects. This is how the painkilling drug morphine works – by mimicking these enkaphalins to produce its potent effects.

Although most studied in humans and other vertebrates, neuropeptides are present in animals across the animal kingdom and, in many cases, have been conserved in families spanning distantly related phyla (the grouping between kingdom and class). And despite hundreds of millions of years of evolution, these neuropeptides can display an ancient conservation of function. For example, it has been shown that the neuropeptides gonadotropin-releasing hormone (GnRH) in humans and adipokinetic hormone (AKH) in the nematode worm C. elegans both have a vital role in the control of reproductive processes.

However, the association of neuropeptides in distantly related phyla is often a difficult task. This is because neuropeptides have short protein sequences, and these sequences have often changed over evolutionary time. It is therefore vital to study animals across the entirety of the animal kingdom, which is now an an exciting possibility in a post-genomic era.

Sea urchins: the bridge

The echinoderms are a phyla of marine animals that include sea urchins, sea cucumbers and starfish and are characterised by a unique shaped body that consists of five identical parts around a central radius. The sea urchin, a small and spiny animal that inhabits ocean floors worldwide, has long been used as a model organism for developmental biology because of its simple organisation, optically transparent embryo and the straightforward process of artificial spawning, fertilisation and rearing, among other things.

Closer to you than a fruit fly. Prilfish, CC BY

However, outside of developmental biology, the sea urchin has also become a valuable tool for understanding neuropeptide evolution. As an echinoderm, the sea urchin is more closely related to humans and other vertebrates than other invertebrates such as the fruit fly D.melanogaster and the nematode worm C. elegans (these species are both used to study human genetics and D. melanogaster has been a particularly vital model organism for studying human genetics). So the sea urchin can be used as an intermediate, to bridge research on these distantly related invertebrate species and vertebrates and can tell us about the evolution of neuropeptide function from a common ancestor.

Moulting insects

The sequencing of the sea urchin genome led to the identification of a number of new neuropeptides including one called NGFFFamide. This neuropeptide was of particular interest, as its precursor – the protein from which the neuropeptide is derived – had a domain that was previously believed to be uniquely associated with an anti-diuretic hormone (vasopressin) and oxytocin, the so-called “love hormone”.

Interestingly, NGFFFamide also appeared to share structural characteristics with a number of other neuropeptides: one called neuropeptide-S (NPS), which is involved in controlling anxiety in humans, one called crustacean cardioactive peptide (CCAP), which is involved in controlling moulting in insects and other arthropods. Both NPS and CCAP bind to receptors that are believed to be descended from the same ancestor. Therefore, the identification of an NPS/CCAP-type receptor in the sea urchin – which we showed to be activated by NGFFFamide – is that “missing link” between previously unassociated signalling systems.

The last common ancestor of humans, sea urchins and insects is likely to have lived over 600m years ago. The remarkable process of evolution means that molecules that once had the same function in this ancestor can, over hundreds of millions of years, change to control highly divergent processes. Investigating these molecules in a range of phyla and species, such as the sea urchin, will continue to help us determine the evolutionary history and origins of important molecules in our brain.