Molecular Mechanisms of Integrative Signal Transduction

Abstract
Our research approach is to identify and characterize signaling mechanisms in specialized cell types as a means
to understand mechanistic underpinnings of various physiological systems. This proposal leverages two
uniquely-suited model systems to ask how cells detect and discriminate diverse environmental signals:
1) Sharks and skates detect and discriminate incredibly weak and specific electric fields using specialized
electroreceptor cells. By exploiting this unique model system, we will ask how cells are molecularly tuned to filter
and select among the subtle differences that specify the most salient environmental signals. Indeed, these fishes
discriminate between small bioelectric signals, such as those from prey or mates, based on their physiological
state. Furthermore, related modulatory hormones can regulate signal detection. Our recent studies have
provided insight regarding the molecular basis of electroreception and suggest that specific ion channel
properties contribute how incoming signals are filtered. Here, will we investigate how electroreceptor protein and
cellular properties are modulated by physiological state to affect cellular signal transduction. We will use genetic
profiling, electrophysiological, and expression cloning methods to probe hormone-induced cellular signaling
cascades and their contribution to cellular electrical tuning. We will then leverage these defined signaling
cascades to ask whether in vivo modulation of cellular tuning determines frequency selectivity in behaving
animals. This approach will reveal how integrative cellular tuning contributes to signal discrimination.
2) In a second project, we will probe mechanisms of signal filtering in octopus arms, which are used as flexible
sentinels that allow these animals to explore their surroundings at a distance by using a unique contact-
dependent form of ‘taste by touch’ chemosensation. Furthermore, octopus arms are capable of processing this
multimodal sensory information, independent of the centralized brain, to produce sophisticated behaviors. Our
studies will use single-cell genetic profiling, physiological, protein structure-function, and natural product
chemistry approaches to identify sensory receptors and their properties, signal transduction cascades, and
intrinsic electrical properties used by specialized cells within arms that facilitate sensation. We will then
independently or simultaneously activate these receptors and signaling cascades to ask how individual receptor
proteins integrate information to produce specific cellular responses and organismal behaviors. This approach
will allow us to determine how single cells detect and transduce multiple stimuli as distinct cellular outputs to
govern organismal function.
These integrative studies span multiple specialized cell types, tissues, and organisms to increase our
understanding of the basic cell biology underlying signal transduction.

Grant Number: 5R35GM142697-05
NIH Institute/Center: NIH
Principal Investigator: Nicholas Bellono