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1000
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Abstract/Summary
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<jats:p>Astrocytes are sensitive to ongoing neuronal/network activities and, accordingly, regulate neuronal functions (synaptic transmission, synaptic plasticity, behavior, etc.) by the context-dependent release of several gliotransmitters (e.g., glutamate, glycine, <jats:sc>D</jats:sc>-serine, ATP). To sense diverse input, astrocytes express a plethora of G-protein coupled receptors, which couple, via G<jats:sub>i/o</jats:sub> and G<jats:sub>q</jats:sub>, to the intracellular Ca<jats:sup>2+</jats:sup> release channel IP<jats:sub>3</jats:sub>-receptor (IP<jats:sub>3</jats:sub>R). Indeed, manipulating astrocytic IP<jats:sub>3</jats:sub>R-Ca<jats:sup>2+</jats:sup> signaling is highly consequential at the network and behavioral level: Depleting IP<jats:sub>3</jats:sub>R subtype 2 (IP<jats:sub>3</jats:sub>R2) results in reduced GPCR-Ca<jats:sup>2+</jats:sup> signaling and impaired synaptic plasticity; enhancing IP<jats:sub>3</jats:sub>R-Ca<jats:sup>2+</jats:sup> signaling affects cognitive functions such as learning and memory, sleep, and mood. However, as a result of discrepancies in the literature, the role of GPCR-IP<jats:sub>3</jats:sub>R-Ca<jats:sup>2+</jats:sup> signaling, especially under physiological conditions, remains inconclusive. One primary reason for this could be that IP<jats:sub>3</jats:sub>R2 has been used to represent all astrocytic IP<jats:sub>3</jats:sub>Rs, including IP<jats:sub>3</jats:sub>R1 and IP<jats:sub>3</jats:sub>R3. Indeed, IP<jats:sub>3</jats:sub>R1 and IP<jats:sub>3</jats:sub>R3 are unique Ca<jats:sup>2+</jats:sup> channels in their own right; they have unique biophysical properties, often display distinct distribution, and are differentially regulated. As a result, they mediate different physiological roles to IP<jats:sub>3</jats:sub>R2. Thus, these additional channels promise to enrich the diversity of spatiotemporal Ca<jats:sup>2+</jats:sup> dynamics and provide unique opportunities for integrating neuronal input and modulating astrocyte–neuron communication. The current review weighs evidence supporting the existence of multiple astrocytic-IP<jats:sub>3</jats:sub>R isoforms, summarizes distinct sub-type specific properties that shape spatiotemporal Ca<jats:sup>2+</jats:sup> dynamics. We also discuss existing experimental tools and future refinements to better recapitulate the endogenous activities of each IP<jats:sub>3</jats:sub>R isoform.</jats:p>
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