The transduction of salient environmental stimuli to the central nervous system depends on the activity of ion channels in electrically excitable cells, a conserved principle throughout all sensory modalities. Understanding how ion currents function is an important goal in basic and clinical science realms. Diverse animal species face the challenge of extracting information from very weak signals as is the case with visual signals in primates, auditory stimuli in barn owls, and mechanosensory information in rodents. Using a sensory system derived from the vestibulocochlear/auditory system, a range of vertebrates detect bioelectric fields which are generated by differential electrical potentials across tissues. Electrosensory systems are particularly well-suited to addressing questions of vestibulocochlear sensory transduction of weak stimuli, especially as it relates to communication. Weakly-electric fish species generate their own stereotyped electric fields as distinct social communication signals. Despite considerable interest in electric fish from a range of biomedical disciplines, mechanistic understanding of their detection of weak electric fields has lagged considerably. During my post- doctoral fellowship, we have elucidated the molecular identity of the ion channel voltage transducers in electroreceptive ?hair cells? found in ampullary organs - the most widespread type of electroreceptor organ. Specifically, we have found that voltage-gated Ca2+ channel 1.3 (Cav1.3) and the large conductance voltage and Ca2+-activated potassium channel (BK) ? both of which are suggested to play an important role in cochlear inner hair cell synaptic transduction - are functionally coupled in electroreceptor cells to transduce and amplify weak electric signals (1 uV over a <200 ms integration time). Here I propose a multi-tiered approach based on these preliminary findings to investigate the contribution of these ion channels to transduction mechanisms in vestibulocochlear-derived electrosensory system.
In Specific Aim 1, I will use state-of-the-art genetic profiling techniques to identify functionally important isoforms of voltage-sensitive ion channels in varied electrosensory periphery and their expression patterns.
In Specific Aim 2, I will use patch-clamp cellular electrophysiology methods to interrogate structurally-specific contributions of candidate ion channels to voltage-sensitive currents.
In Specific Aim 3, I will behaviorally examine the sensory contribution of these channels to feedback necessary to produce a distinct communication signal. The results of this proposal will shed light on the synaptic contributions of ion channels such as Cav1.3 and BK channels to receptor cell transduction mechanisms, specifically in a hair-cell related system. Central to the success of this proposal, I will be mentored by Dr. David Julius well as expert advisors in auditory (Dr. Christoph Schreiner), electrosensory (Dr. Bruce Carlson) systems, and genetic profiling (Dr. Nick Ingolia) to develop skills in advanced transcriptional analyses, cellular electrophysiology, and communication behavior, providing me with the skill set necessary to embark on a career as an independent scientist.
The transduction of salient environmental stimuli to the central nervous system is dependent upon the activity of ion channels in electrically excitable cells, and this principle is conserved among all sensory modalities including auditory and electrosensory systems. During my postdoctoral fellowship, I identified and functionally characterized two ion channels (Cav1.3 and BK) responsible for the transduction and oscillatory amplification of weak electric fields in elasmobranch fish electroreceptors (homologs to the mechanosensory cochlear inner ear hair cells), and here I propose to examine identify patterns of gene regulation and expression, ion channel adaptive functional properties, and the behavioral consequences of ion channel activity in communication. Through the K99 phase of this proposal, I will gain integral skills related to these aims in transcriptional analyses, cellular physiology, and communication behavior that will enable me to establish an independent research program revolving around ion channel contributions to sensory transduction mechanisms in communication-related senses.
|Bellono, Nicholas W; Leitch, Duncan B; Julius, David (2018) Molecular tuning of electroreception in sharks and skates. Nature 558:122-126|