Dataset Information

L-type voltage-gated Ca²⁺ channel Ca_V1.2 regulates chondrogenesis during limb development.

ABSTRACT: All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V _mem), and have the capacity to modulate V _mem and respond to their own and neighbors' changes in V _mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V _mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V _mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V _mem increases intracellular Ca²⁺ signaling through Ca²⁺ influx, via Ca_V1.2, 1 of L-type voltage-gated Ca²⁺ channels (VGCCs). We find that Ca_V1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of Ca_V1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca²⁺-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca²⁺ signaling, partly rescues Sox9 expression. These data reveal instructive roles of Ca_V1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation.

SUBMITTER: Atsuta Y

PROVIDER: S-EPMC6815189 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during limb development.

Atsuta Yuji Y Tomizawa Reiko R RR Levin Michael M Tabin Clifford J CJ

Proceedings of the National Academy of Sciences of the United States of America 20191007 43

All cells, including nonexcitable cells, maintain a discrete transmembrane potential (Vmem), and have the capacity to modulate Vmem and respond to their own and neighbors' changes in Vmem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in Vmem are converted into intracellular inputs that in turn ...[more]

PMID: 31591237

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Project description:Voltage-gated Cav1.2 and Cav1.3 (L-type) Ca2+ channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca2+-dependent facilitation of voltage-gated Cav1.3 Ca2+ channels in transfected cells. Mice lacking densin (densin KO) exhibit defects in synaptic plasticity, spatial memory, and increased anxiety-related behaviors-phenotypes that more closely match those in mice lacking Cav1.2 than Cav1.3. Therefore, we investigated the functional impact of densin on Cav1.2. We report that densin is an essential regulator of Cav1.2 in neurons, but has distinct modulatory effects compared with its regulation of Cav1.3. Densin binds to the N-terminal domain of Cav1.2, but not that of Cav1.3, and increases Cav1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Cav1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Cav1.2 channels, overexpression of densin increases the clustering of Cav1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Cav1.2 in the brain, as well as Cav1.2 current density and signaling to the nucleus, are reduced in neurons from densin KO mice. We conclude that densin is an essential regulator of neuronal Cav1 channels and ensures efficient Cav1.2 Ca2+ signaling at excitatory synapses.SIGNIFICANCE STATEMENT The number and localization of voltage-gated Cav Ca2+ channels are crucial determinants of neuronal excitability and synaptic transmission. We report that the protein densin-180 is highly enriched at excitatory synapses in the brain and enhances the cell surface trafficking and postsynaptic localization of Cav1.2 L-type Ca2+ channels in neurons. This interaction promotes coupling of Cav1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Cav1.2 in regulating cognition and mood.

Dataset Information

L-type voltage-gated Ca²⁺ channel Ca_V1.2 regulates chondrogenesis during limb development.

Publications

L-type voltage-gated Ca<sup>2+</sup> channel Ca<sub>V</sub>1.2 regulates chondrogenesis during limb development.

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