Fish-Human Hybrid Hormone Receptors Reveal How Animals Left The Oceans

There were few bigger moments in the history of life than when the first fish crawled out of the ocean. Many changes were required for this to happen, and one of the least obvious is also among the most important – the capacity to retain salt. This development was built on the change of a single amino acid, reversing the operation of a receptor.

When we think of what it took for vertebrates to conquer the land, the capacity to breath air and crawl spring to mind. Biochemists, on the other hand, note for the first time that animals needed to confront a shortage of salt.

“Salt is incredibly important. It is essential for animals with a vascular system as it ensures they maintain a healthy blood pressure,” said Professor Peter Fuller of Australia's Hudson Institute in an emailed statement. This trait evolved when our ancestors had access to abundant salt all around them. As animals moved onto land, however, they needed to either develop alternative ways to sustain blood without salt or retain the more limited quantities they could access. The latter proved the more viable evolutionary path, but the quest for sufficient salt has driven land animals ever since.

The kidneys are key to salt retention, avoiding flushing out too much of what they extract from blood plasma. This process is controlled by the mineralocorticoid receptor (MR), but in fish the receptor acts in the reverse way, causing them to eliminate excess sodium.

Most strangely of all, fish MR are triggered in the opposite way to those in humans and other terrestrial animals; hormones that turn the MR on in fish, turn it off in humans and vice versa.

In Proceedings of the National Academy of Sciences, Fuller describes creating a hybrid or chimera MR that was part zebrafish and part human, allowing him and his colleagues to zoom in on the differences between the two. Fuller found a single amino acid change (threonine replacing leucine) flipped the receptor's functioning.

Salt retention appears to be an important trait for animals living in freshwater as well as land, but Fuller told IFLScience the literature on the transition from salt to freshwater is unclear. Consequently, we don't know if the leucine to threonine shift took place so a fish could inhabit a river, with its descendants using the capacity for salt-retention to move onto land.

With hypertension associated with a high-salt diet a major killer, Fuller hopes his work will inspire new ideas on how to make the body retain less salt when necessary. “We may be able to design drugs that target previously unrecognized interactions within the receptor, rather than just blocking it,” he told IFLScience.