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Alternative Mechanisms for Fast Na⁺/Ca²⁺ Signaling in Eukaryotes via a Novel Class of Single-Domain Voltage-Gated Channels.

ABSTRACT: Rapid Na⁺/Ca²⁺-based action potentials govern essential cellular functions in eukaryotes, from the motile responses of unicellular protists, such as Paramecium [1, 2], to complex animal neuromuscular activity [3]. A key innovation underpinning this fundamental signaling process has been the evolution of four-domain voltage-gated Na⁺/Ca²⁺ channels (4D-Ca_vs/Na_vs). These channels are widely distributed across eukaryote diversity [4], albeit several eukaryotes, including land plants and fungi, have lost voltage-sensitive 4D-Ca_v/Na_vs [5-7]. Because these lineages appear to lack rapid Na⁺/Ca²⁺-based action potentials, 4D-Ca_v/Na_vs are generally considered necessary for fast Na⁺/Ca²⁺-based signaling [7]. However, the cellular mechanisms underpinning the membrane physiology of many eukaryotes remain unexamined. Eukaryotic phytoplankton critically influence our climate as major primary producers. Several taxa, including the globally abundant diatoms, exhibit membrane excitability [8-10]. We previously demonstrated that certain diatom genomes encode 4D-Ca_v/Na_vs [4] but also proteins of unknown function, resembling prokaryote single-domain, voltage-gated Na⁺ channels (BacNa_vs) [4]. Here, we show that single-domain channels are actually broadly distributed across major eukaryote phytoplankton lineages and represent three novel classes of single-domain channels, which we refer collectively to as EukCats. Functional characterization of diatom EukCatAs indicates that they are voltage-gated Na⁺- and Ca²⁺-permeable channels, with rapid kinetics resembling metazoan 4D-Ca_vs/Na_vs. In Phaeodactylum tricornutum, which lacks 4D-Ca_v/Na_vs, EukCatAs underpin voltage-activated Ca²⁺ signaling important for membrane excitability, and mutants exhibit impaired motility. EukCatAs therefore provide alternative mechanisms for rapid Na⁺/Ca²⁺ signaling in eukaryotes and may functionally replace 4D-Ca_vs/Na_vs in pennate diatoms. Marine phytoplankton thus possess unique signaling mechanisms that may be key to environmental sensing in the oceans.

SUBMITTER: Helliwell KE

PROVIDER: S-EPMC6509283 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Inherited retinal degenerations (IRDs) are a group of untreatable and commonly blinding diseases characterized by progressive photoreceptor loss. IRD pathology has been linked to an excessive activation of cyclic nucleotide-gated channels (CNGC) leading to Na+- and Ca2+-influx, subsequent activation of voltage-gated Ca2+-channels (VGCC), and further Ca2+ influx. However, a connection between excessive Ca2+ influx and photoreceptor loss has yet to be proven.Here, we used whole-retina and single-cell RNA-sequencing to compare gene expression between the rd1 mouse model for IRD and wild-type (wt) mice. Differentially expressed genes indicated links to several Ca2+-signalling related pathways. To explore these, rd1 and wt organotypic retinal explant cultures were treated with the intracellular Ca2+-chelator BAPTA-AM or inhibitors of different Ca2+-permeable channels, including CNGC, L-type VGCC, T-type VGCC, Ca2+-release-activated channel (CRAC), and Na+/Ca2+ exchanger (NCX). Moreover, we employed the novel compound NA-184 to selectively inhibit the Ca2+-dependent protease calpain-2. Effects on the retinal activity of poly(ADP-ribose) polymerase (PARP), sirtuin-type histone-deacetylase, calpains, as well as on activation of calpain-1, and - 2 were monitored, cell death was assessed via the TUNEL assay.While rd1 photoreceptor cell death was reduced by BAPTA-AM, Ca2+-channel blockers had divergent effects: While inhibition of T-type VGCC and NCX promoted survival, blocking CNGCs and CRACs did not. The treatment-related activity patterns of calpains and PARPs corresponded to the extent of cell death. Remarkably, sirtuin activity and calpain-1 activation were linked to photoreceptor protection, while calpain-2 activity was related to degeneration. In support of this finding, the calpain-2 inhibitor NA-184 protected rd1 photoreceptors.These results suggest that Ca2+ overload in rd1 photoreceptors may be triggered by T-type VGCCs and NCX. High Ca2+-levels likely suppress protective activity of calpain-1 and promote retinal degeneration via activation of calpain-2. Overall, our study details the complexity of Ca2+-signalling in photoreceptors and emphasizes the importance of targeting degenerative processes specifically to achieve a therapeutic benefit for IRDs. Video Abstract.

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Alternative Mechanisms for Fast Na⁺/Ca²⁺ Signaling in Eukaryotes via a Novel Class of Single-Domain Voltage-Gated Channels.

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Alternative Mechanisms for Fast Na+/Ca2+ Signaling in Eukaryotes via a Novel Class of Single-Domain Voltage-Gated Channels.

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OmicsDI is part of the ELIXIR infrastructure

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Alternative Mechanisms for Fast Na⁺/Ca²⁺ Signaling in Eukaryotes via a Novel Class of Single-Domain Voltage-Gated Channels.