Highlights d A given stimulus preferentially activates a single TrpA1 isoform in vivo d Polymodal nociception requires co-expression of TrpA1 isoforms in nociceptors d Each TrpA1 isoform has a unique expression profile d isoEXPRESS is a new and versatile framework targeting alternative splicing

The cation channel transient receptor potential vanilloid 4 (TRPV4) is one of the few identified ion channels that can directly cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here, we show that in vivo expression of a neuropathy-causing TRPV4 mutant (TRPV4R269C) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4R269C triggers increased intracellular Ca2+ through a Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca2+ and neurotoxicity in Drosophila and cultured primary mouse neurons. Importantly, TRPV4 activity impairs axonal mitochondrial transport, and TRPV4-mediated neurotoxicity is modulated by the Ca2+-binding mitochondrial GTPase Miro. Our data highlight an integral role for CaMKII in neuronal TRPV4-associated Ca2+ responses, the importance of tightly regulated Ca2+ dynamics for mitochondrial axonal transport, and the therapeutic promise of TRPV4 antagonists for patients with TRPV4-related neurodegenerative diseases.

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Injured neurons exhibit cell type-specific axon regeneration, but the underlying mechanisms remain elusive. Two subtypes of Drosophila sensory neurons show distinct regenerative competence. Here, we show that axotomy induces long-lasting burst firing and Ca 2+ spikes specifically in the regenerative subtype. Genetic silencing of firing in the regenerative subtype inhibits regeneration. Optogenetic stimulation of the nonregenerative subtype reveals that activity patterns critically determine regeneration; burst firing triggers Ca 2+ spikes and suffices to induce regeneration, while tonic firing fails to induce Ca 2+ spikes and regeneration. We further show the L-type Ca 2+ channel, Dmca1D, regulates Ca 2+ spikes and regeneration. Intriguingly, the regenerative neuronal subtype expresses higher levels of Dmca1D, and overexpression of Dmca1D in the non-regenerative subtype facilitates regeneration. Our studies indicate that injury induces cell type-specific neuronal activities, which act through Ca 2+ spikes to govern regeneration, and suggest that precise control of neuronal activity patterns is an effective way to promote regeneration.

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