Expanding the Neuron's Calcium Signaling Repertoire: Intracellular Calcium Release via Voltage-Induced PLC and IP3R Activation

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Abstract
Neuronal calcium acts as a charge carrier during information processing and as a ubiquitous intracellular messenger. Calcium signals are fundamental to numerous aspects of neuronal development and plasticity. Specific and independent regulation of these vital cellular processes is achieved by a rich bouquet of different calcium signaling mechanisms within the neuron, which either can operate independently or may act in concert. This study demonstrates the existence of a novel calcium signaling mechanism by simultaneous patch clamping and calcium imaging from acutely isolated central neurons. These neurons possess a membrane voltage sensor that, independent of calcium influx, causes G-protein activation, which subsequently leads to calcium release from intracellular stores via phospholipase C and inositol 1,4,5-trisphosphate receptor activation. This allows neurons to monitor activity by intracellular calcium release without relying on calcium as the input signal and opens up new insights into intracellular signaling, developmental regulation, and information processing in neuronal compartments lacking calcium channels. In neurons, calcium ions play a dual role as charge carriers and intracellular messengers, thereby linking brain activity to cellular changes. Alterations in the electrical potential across the cell's outer membrane (as happens, for example, when a neuron fires an action potential), can induce an influx of calcium ions through voltage-dependent membrane channels, which in turn regulate multiple cellular processes, such as gene transciption, cytoskeletal rearrangements, or even cell death. Stores of calcium ions also exist within neurons, which release their contents in response to multiple intracellular signals, including calcium itself. Here, we demonstrate that the neuronal cell membrane also possesses a voltage sensor that activates an intracellular calcium-release mechanism. This sensor enables neurons to recruit intracellular calcium signaling pathways in response to electrical activity without relying on calcium channels in their membrane. As large parts of a neuron's membrane may not contain calcium channels, this novel mechanism adds previously unanticipated calcium signaling possibilities to the neuron's intracellular communication machinery.