Astrocytic IPRs: Beyond IPR2.

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, D-serine, ATP). To sense diverse input, astrocytes express a plethora of G-protein coupled receptors, which couple, via G and G, to the intracellular Ca release channel IP-receptor (IPR). Indeed, manipulating astrocytic IPR-Ca signaling is highly consequential at the network and behavioral level: Depleting IPR subtype 2 (IPR2) results in reduced GPCR-Ca signaling and impaired synaptic plasticity; enhancing IPR-Ca 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-IPR-Ca signaling, especially under physiological conditions, remains inconclusive. One primary reason for this could be that IPR2 has been used to represent all astrocytic IPRs, including IPR1 and IPR3. Indeed, IPR1 and IPR3 are unique Ca 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 IPR2. Thus, these additional channels promise to enrich the diversity of spatiotemporal Ca 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-IPR isoforms, summarizes distinct sub-type specific properties that shape spatiotemporal Ca dynamics. We also discuss existing experimental tools and future refinements to better recapitulate the endogenous activities of each IPR isoform.