Illustrated by Vickie Nguyen

How to Taste With Your Arms: Chemotactile Receptors, from Biophysics to Evolution

Amy Li | SQ 2023-2024

How to Taste With Your Arms: Chemotactile Receptors, from Biophysics to Evolution

A shrimp pounding against the wall of its tank, as if it knows what is to come. In the opposite corner: an octopus, its arms probing the surfaces of their enclosure. It meanders, seemingly aimless but for its searching arms. Water, rippling. Suddenly the octopus lunges, as if it has caught the shrimp’s scent. You already know what happens next. Except—how did the octopus ‘smell’ the doomed shrimp? Well, by ‘tasting’ it.

A biologist looks on, curiosity — that lifeblood of science — sparked.

Wading in: Cephalopods and Structural Biology

If fish were gamblers, coleoid cephalopods would win the evolutionary jackpot (note that cephalopods are not technically fishes).1 Boasting the largest nervous systems observed in invertebrates, coleoid cephalopods — a phylogenetic subclass that comprises octopus, squid, and cuttlefish — are the ocean’s darlings. With sophisticated behaviors arising from their complex nervous systems, cephalopods have long fascinated scientists. However, their evolution remains poorly understood, and particularly murky is the molecular basis for the substantial behavioral diversity across the 750-some species of cephalopods.1,2

One interesting behavioral difference between octopus and squid lineages is found in their feeding strategies. The eight-armed octopus feels along the seafloor to find its food, while the squid conceals itself before springing into action to capture prey with hook-like suckers on its eight arms and two longer tentacles.3 What adaptations underpin this difference?

The answer lies in chemotactile receptors (CRs), a cephalopod-specific family of proteins that the Bellono Lab at Harvard University first reported in 2020.4 These CRs are expressed in sensory cells on the outer lining of cephalopod arms and tentacle suckers (at a greater level in octopus than in squid), and were found to play a role in prey detection.4 CRs share sequence similarities with nicotinic acetylcholine receptors, a crucial ligand-gated ion channel found at the neuromuscular junction.3 Nicotinic receptors are found in many animals, including humans, and activate muscle contraction when they bind to acetylcholine, a neurotransmitter released by neurons. Well-known for their work on the structural biology of nicotinic receptors, the Hibbs Lab at UC San Diego was approached by the Bellono Lab to collaborate on characterizing the newly discovered CRs.

The Hibbs Lab, previously located at the UT Southwestern Medical Center, moved to UC San Diego in 2023. Headed by UC San Diego alumnus Dr. Ryan Hibbs, the lab focuses on the biophysics and pharmacology of nicotinic and GABAA receptors as well as their involvement in certain autoimmune disorders. Using cryogenic electron microscopy (cryo-EM), the lab constructs high-resolution images of ion channels to understand how they work, putting into practice the oft-repeated biological maxim “structure determines function.”

The Plunge: Active Site Structures

Using the cryo-EM images, the lab confirmed that octopus and squid CRs, like nicotinic receptors, are ligand-gated cation channels. When a ligand binds to the receptor, its channel opens, and positively charged ions like sodium and potassium move across the membrane. This leads to depolarization, generating an action potential — the basis of fast electrical signaling. CRs and nicotinic receptors bind ligands at the same site, located in the extracellular domain. However, the CR site does not bind to acetylcholine as the nicotinic receptor site does. A few key alterations render CRs insensitive to acetylcholine: one loop of residues (amino acids that are part of a protein chain) is shorter due to missing tyrosine residues and a missing disulfide bond.3,7

The Unexplored Depths

Only recently discovered, CRs still present numerous avenues for future research. One potential direction is to investigate marine natural products. The CRB1 ligand denatonium does not occur naturally in squid’s prey — it is a commercially available bitter compound (also used in Nintendo Switches to prevent children from eating the game cards).9 The Hibbs Lab is potentially acquiring marine natural products from the Scripps Institute of Oceanography, which would enable investigations of truer-to-life CR interactions with its ligands.

Conclusion

The Hibbs Lab’s biophysical analysis helps unravel how CRs diverged from the ancestral nicotinic receptor, pivoting from neurotransmitter receptor to sensory receptor; and how sensory specialization affects behavior, which in turn drives octopuses and squids to fill different ecological niches.3 While CRs are one factor among many, it is remarkable that the evolution of these two cephalopod lineages — a grand process with a time frame of hundreds of millions of years — can be traced down to specific amino acid modifications in one receptor family. Thanks to the collaborative nature of this study, researchers from UC San Diego and Harvard were able to synthesize their different areas of expertise into a multilevel understanding of octopus and squid: from the molecular to the behavioral and evolutionary.

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