Faculty Collaboration Database

Opposing roles of voltage-gated Ca2+ channels in neuronal control of regenerative patterning. J Neurosci 2011 Nov 02;31(44):15983-95

Date

11/04/2011

Pubmed ID

22049441

Pubmed Central ID

PMC3380623

DOI

10.1523/JNEUROSCI.3029-11.2011

Scopus ID

2-s2.0-80155134773 (requires institutional sign-in at Scopus site)   42 Citations

Abstract

There is intense interest in developing methods to regulate proliferation and differentiation of stem cells into neuronal fates for the purposes of regenerative medicine. One way to do this is through in vivo pharmacological engineering using small molecules. However, a key challenge is identification of relevant signaling pathways and therein druggable targets to manipulate stem cell behavior efficiently in vivo. Here, we use the planarian flatworm as a simple chemical-genetic screening model for nervous system regeneration to show that the isoquinoline drug praziquantel (PZQ) acts as a small molecule neurogenic to produce two-headed animals with integrated CNSs following regeneration. Characterization of the entire family of planarian voltage-operated Ca(2+) channel α subunits (Ca(v)α), followed by in vivo RNAi of specific Ca(v) subunits, revealed that PZQ subverted regeneration by activation of a specific voltage-gated Ca(2+) channel isoform (Ca(v)1A). PZQ-evoked Ca(2+) entry via Ca(v)1A served to inhibit neuronally derived Hedgehog signals, as evidenced by data showing that RNAi of Ca(v)1A prevented PZQ-evoked bipolarity, Ca(2+) entry, and decreases in wnt1 and wnt11-5 levels. Surprisingly, the action of PZQ was opposed by Ca(2+) influx through a closely related neuronal Ca(v) isoform (Ca(v)1B), establishing a novel interplay between specific Ca(v)1 channel isoforms, Ca(2+) entry, and neuronal Hedgehog signaling. These data map PZQ efficacy to specific neuronal Ca(v) complexes in vivo and underscore that both activators (Ca(v)1A) and inhibitors (Ca(v)1B) of Ca(2+) influx can act as small molecule neurogenics in vivo on account of the unique coupling of Ca(2+) channels to neuronally derived polarity cues.

Author List

Zhang D, Chan JD, Nogi T, Marchant JS

Author

Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Genetically Modified
Anthelmintics
Behavior, Animal
Calcium
Calcium Channels, L-Type
Cytoskeletal Proteins
Feeding Behavior
Nerve Regeneration
Nervous System
Neurons
Planarians
Praziquantel
RNA Interference
Sequence Alignment
Signal Transduction
Wnt1 Protein
beta Catenin