Characterization of two neuronal subclasses through constellation pharmacology

Different types of neurons diverge in function because they express their own unique set or constellation of signaling molecules, including receptors and ion channels that work in concert. We describe an approach to identify functionally divergent neurons within a large, heterogeneous neuronal popul...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2012-07, Vol.109 (31), p.12758-12763
Hauptverfasser: Teichert, Russell W, Raghuraman, Shrinivasan, Memon, Tosifa, Cox, Jeffrey L, Foulkes, Tucker, Rivier, Jean E, Olivera, Baldomero M
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container_end_page 12763
container_issue 31
container_start_page 12758
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 109
creator Teichert, Russell W
Raghuraman, Shrinivasan
Memon, Tosifa
Cox, Jeffrey L
Foulkes, Tucker
Rivier, Jean E
Olivera, Baldomero M
description Different types of neurons diverge in function because they express their own unique set or constellation of signaling molecules, including receptors and ion channels that work in concert. We describe an approach to identify functionally divergent neurons within a large, heterogeneous neuronal population while simultaneously investigating specific isoforms of signaling molecules expressed in each. In this study we characterized two subclasses of menthol-sensitive neurons from cultures of dissociated mouse dorsal-root ganglia. Although these neurons represent a small fraction of the dorsal-root ganglia neuronal population, we were able to identify them and investigate the cell-specific constellations of ion channels and receptors functionally expressed in each subclass, using a panel of selective pharmacological tools. Differences were found in the functional expression of ATP receptors, TRPA1 channels, voltage-gated calcium-, potassium-, and sodium channels, and responses to physiologically relevant cold temperatures. Furthermore, the cell-specific responses to various stimuli could be altered through pharmacological interventions targeted to the cell-specific constellation of ion channels expressed in each menthol-sensitive subclass. In fact, the normal responses to cold temperature could be reversed in the two neuronal subclasses by the coapplication of the appropriate combination of pharmacological agents. This result suggests that the functionally integrated constellation of signaling molecules in a particular type of cell is a more appropriate target for effective pharmacological intervention than a single signaling molecule. This shift from molecular to cellular targets has important implications for basic research and drug discovery. We refer to this paradigm as “constellation pharmacology.”
doi_str_mv 10.1073/pnas.1209759109
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subjects Adenosine triphosphatase
adenosine triphosphate
Animals
Antipruritics - pharmacology
Biological Sciences
Calcium
Cells
cold
Cold Temperature
drugs
Experimentation
ganglia
Ganglia, Spinal - cytology
Ganglia, Spinal - metabolism
Gene Expression Regulation - drug effects
Gene Expression Regulation - immunology
Ion channels
Menthol - pharmacology
Mice
Mice, Knockout
Molecules
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
Neurons
Neurons - cytology
Neurons - metabolism
Pain
Pharmacology
Protein isoforms
Receptors
Rodents
Sodium channels
temperature
Transient Receptor Potential Channels - biosynthesis
Transient Receptor Potential Channels - genetics
TRPA1 Cation Channel
title Characterization of two neuronal subclasses through constellation pharmacology
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