# Structural basis for sensory receptor function

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $613,114

## Abstract

PROJECT SUMMARY
This proposal leverages cephalopods as a uniquely suited model system to ask how sensory systems detect
and discriminate diverse environmental signals. Octopuses, as representative cephalopods, use their flexible
arms and semi-autonomous distributed nervous system to explore their surroundings at a distance by locally
detecting and capturing prey. This unique “taste by touch” system is mediated by chemotactile receptors (CRs),
which are structurally similar to nicotinic acetylcholine receptors, but are insensitive to neurotransmitters, and
instead detect poorly soluble molecules to mediate contact-dependent aquatic sensation. Here, we will exploit
cephalopod chemotactile systems to understand how subtle evolutionary modifications in single proteins
facilitate a functional transition from neuronal signaling to environmental sensation. Our approach spans
structural biology to animal behavior. First, in Aim 1, we propose to determine high resolution structures of ligand-
bound and apo octopus CRs to analyze structural and biophysical underpinnings of sensory versus
neurotransmitter receptor function. In Aim 2, we will extend our comparative approach to CRs in distinct
cephalopods with specific behaviors. In contrast to octopuses that use arms for active exploration, cuttlefish are
ambush predators that strike and capture unsuspecting prey with their eight arms and two long tentacles. We
recently discovered CRs in cuttlefish, which detect distinct ligands, exhibit different voltage dependence, and
enable unique behaviors. Here, we will extend our analyses to include structurally informed experiments to
compare aspects of ligand binding, ion permeation, and channel gating to ask how receptor function is suited to
particular organismal behaviors. Finally, we recently found that octopus sensory cells express diverse CR subunit
combinations that can form homo- and heteropentameric ion channel complexes. Subunit composition alters
ligand sensitivity and ion permeation to tune signal detection, transduction, and filtering to influence peripheral
processing in the octopus’ unusual distributed nervous system. In Aim 3, we will analyze the structural basis by
which heteromeric complexes alter biophysical properties of ligand binding, ion permeation, and channel gating.
Collectively, these studies will reveal broad principles underlying the structural basis for sensory receptor function
and the evolution of biological novelty. Moreover, comparisons between cephalopod CRs and related
mammalian neurotransmitter receptors will define core channel architecture for insights regarding conserved
pharmacological targets.

## Key facts

- **NIH application ID:** 10733574
- **Project number:** 7R01NS129060-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Nicholas Bellono
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $613,114
- **Award type:** 7
- **Project period:** 2022-09-21 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10733574

## Citation

> US National Institutes of Health, RePORTER application 10733574, Structural basis for sensory receptor function (7R01NS129060-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10733574. Licensed CC0.

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