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TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3.

ABSTRACT: Astrocytes contribute to the formation and function of synapses and are found throughout the brain, where they show intracellular store-mediated Ca(2+) signals. Here, using a membrane-tethered, genetically encoded calcium indicator (Lck-GCaMP3), we report the serendipitous discovery of a new type of Ca(2+) signal in rat hippocampal astrocyte-neuron cocultures. We found that Ca(2+) fluxes mediated by transient receptor potential A1 (TRPA1) channels gave rise to frequent and highly localized 'spotty' Ca(2+) microdomains near the membrane that contributed appreciably to resting Ca(2+) in astrocytes. Mechanistic evaluations in brain slices showed that decreases in astrocyte resting Ca(2+) concentrations mediated by TRPA1 channels decreased interneuron inhibitory synapse efficacy by reducing GABA transport by GAT-3, thus elevating extracellular GABA. Our data show how a transmembrane Ca(2+) source (TRPA1) targets a transporter (GAT-3) in astrocytes to regulate inhibitory synapses.

SUBMITTER: Shigetomi E

PROVIDER: S-EPMC3282183 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3.

Shigetomi Eiji E Tong Xiaoping X Kwan Kelvin Y KY Corey David P DP Khakh Baljit S BS

Nature neuroscience 20111211 1

Astrocytes contribute to the formation and function of synapses and are found throughout the brain, where they show intracellular store-mediated Ca(2+) signals. Here, using a membrane-tethered, genetically encoded calcium indicator (Lck-GCaMP3), we report the serendipitous discovery of a new type of Ca(2+) signal in rat hippocampal astrocyte-neuron cocultures. We found that Ca(2+) fluxes mediated by transient receptor potential A1 (TRPA1) channels gave rise to frequent and highly localized 'spot ...[more]

PMID: 22158513

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Project description:The sigma 1 receptor (?1R) and the mu-opioid receptor (MOR) regulate the transient receptor potential (TRP) V1 calcium channel. A series of proteins are involved in the cross-regulation between MORs and calcium channels like the glutamate N-methyl-D-aspartate receptor (NMDAR), including the histidine triad nucleotide-binding protein 1 (HINT1), calmodulin (CaM), and the ?1R. Thus, we assessed whether similar mechanisms also apply to the neural TRP ankyrin member 1 (TRPA1), TRP vanilloid member 1 (TRPV1), and TRP melastatin member 8 (TRPM8). Our results indicate that ?1R and CaM bound directly to cytosolic regions of these TRPs, and this binding increased in the presence of calcium. By contrast, the association of HINT1 with these TRPs was moderately dependent on calcium. The ?1R always competed with CaM for binding to the TRPs, except for its binding to the TRPA1 C-terminal where ?1R binding cooperated with that of CaM. However, ?1R dampened HINT1 binding to the TRPA1 N-terminal. When the effect of ?1R ligands was addressed, the ?1R agonists PRE084 and pregnenolone sulfate enhanced the association of the ?1R with the TRPM8 N-terminal and TRPV1 C-terminal in the presence of physiological calcium, as seen for the ?1R-NMDAR interactions. However, these agonists dampened ?1R binding to the TRPA1 and TRPV1 N-terminal domains, and also to the TRPA1 C-terminal, as seen for ?1R-binding immunoglobulin protein (BiP) interactions in the endoplasmic reticulum (ER). By contrast, the ?1R antagonists progesterone and S1RA reduced the association of ?1R with TRPA1 and TRPV1 C-terminal regions, as seen for the ?1R-NMDAR interactions. Conversely, they enhanced the ?1R interaction with the TRPA1 N-terminal, as seen for ?1R-BiP interactions, whereas they barely affected the association of ?1R with the TRPV1 N-terminal. Thus, depending on the calcium channel and the cytosolic region examined, the ?1R agonists pregnenolone sulfate and PRE084 opposed or collaborated with the ?1R antagonists progesterone and S1RA to disrupt or promote such interactions. Through the use of cloned cytosolic regions of selected TRP calcium channels, we were able to demonstrate that ?1R ligands exhibit biased activity to regulate particular ?1R interactions with other proteins. Since ?1Rs are implicated in essential physiological processes, exploiting such ligand biases may represent a means to develop more selective and efficacious pharmacological interventions.

Dataset Information

TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3.

Publications

TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3.

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